Cyclin Expression
Published by Anonymous on 2007/9/29 (3117 reads)
1: Cancer Sci. 2007 May;98(5):629-35. Epub 2007 Mar 14.
Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression.
Tashiro E, Tsuchiya A, Imoto M.
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan.
Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed.
Publication Types:
Review
PMID: 17359287 [PubMed - indexed for MEDLINE]
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2: Pneumonol Alergol Pol. 2005;73(3):297-300.
[Clinical significance of cyclin Dl expression in non-small cell lung cancer]
[Article in Polish]
Dworakowska D.
Klinika Chorób Wewnqtrznych, Endokrynologii i Zaburzeń Hemostazy, AM w Gdańsku. ddw@amg.gda.pl
Lung cancer remains interdisciplinary problem. The genetic alterations in non-small cell lung cancer (NSCLC) are related to tumor suppressor genes and proto-oncogenes. CCND1 gene, coding cyclin DI, in correlation with pRb is involved in regulation of cell cycle arrest in G1 phase. Amplification of CCND1 gene and cyclin D1 over-expression was found in several cancers including head and neck cancers or colorectal cancer, where these alterations were correlated with worse prognosis. The literature addressing the clinical significance of CCND1 gene amplification/expression in NSCLC remains poor and prognostic value of these alterations in that cancer is still controversial.
Publication Types:
English Abstract
Review
PMID: 16989170 [PubMed - indexed for MEDLINE]
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3: Cell Cycle. 2006 Mar;5(5):472-7. Epub 2006 Mar 1.
Do truncated cyclins contribute to aberrant cyclin expression in cancer?
Van Dross R, Browning PJ, Pelling JC.
Department of Pharmacology and Toxicology, Leo Jenkins Cancer Center, East Carolina University, Greenville, North Carolina 27834, USA. vandrossr@ecu.edu
Cyclin overexpression is found in several types of cancer. Genetic events that place cyclin genes under the control of active promoters or that increase cyclin gene copy number account for most instances of cyclin overexpression. New paradigms for aberrant cyclin expression have been suggested by studies showing that truncated cyclins are expressed in specific subsets of cancer. The altered cyclins lack regulatory sequences (compared to the wild-type protein) that modulate their stability, subcellular localization or cdk-associated kinase activity. In this communication, we review the current literature and assess the role of truncated cyclins D, E, A, B, C and virus encoded-cyclin D (K-cyclin) in the development of cancer. We also report the molecular characteristics, expression patterns and if available, prognostic significance of these proteins.
Publication Types:
Review
PMID: 16552186 [PubMed - indexed for MEDLINE]
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4: Cancer Metastasis Rev. 2005 Sep;24(3):383-93.
Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression.
Walker JL, Assoian RK.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Integrins and growth factor receptors coordinately regulate proliferation in nontransformed cells. Coordinate signaling from these receptors controls the activation of the G1 phase cyclin-dependent kinases, largely by regulating levels of cyclin D1 and p27(kip1). Induction of cyclin D1 is one of the best understood examples of an integrin/growth factor receptor-regulated G1 phase target. This review focuses on the integrin-dependent signal transduction events that regulate the expression of cyclin D1 during G1 phase.
Publication Types:
Research Support, N.I.H., Extramural
Review
PMID: 16258726 [PubMed - indexed for MEDLINE]
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5: Clin Otolaryngol Allied Sci. 2004 Dec;29(6):698-704.
Molecular markers in dysplasia of the larynx: expression of cyclin-dependent kinase inhibitors p21, p27 and p53 tumour suppressor gene in predicting cancer risk.
Jeannon JP, Soames JV, Aston V, Stafford FW, Wilson JA.
Department of Otolaryngology Head and Neck Surgery, University of Newcastle-upon-Tyne, Tyne and Wear, UK. jpjeannon@doctors.org.uk
Premalignant conditions affect the larynx. Dysplasia can progress in severity resulting in cancer depending on many clinical, pathological and molecular factors. The purpose of this study was to examine the expression of the p21 and p27 cyclin-dependent kinase inhibitors and p53 tumour suppressor gene in dysplasia of the larynx. A total of 114 cases of untreated dysplasia were selected from the archives of the University of Newcastle. p21, p27 and p53 immunohistochemistry was performed and the cases followed up. Twenty-eight dysplasias (24%) subsequently developed into cancers. Expression of the molecular factors studied was not associated with cancer progression. p53 expression was associated with smoking (P = 0.005). In contrast, grade of dysplasia was significantly associated with cancer risk (odds ratio 6.7; P = 0.0001). The majority (75%) of cancers were detected within 12 months of dysplasia being diagnosed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15533163 [PubMed - indexed for MEDLINE]
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6: Gene. 2004 Aug 4;337:15-23.
Cellular control of gene expression by T-type cyclin/CDK9 complexes.
Garriga J, Graña X.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad St., Philadelphia, PA 19140, USA.
The family of Cyclin-Dependent Kinases (CDKs) can be subdivided into two major functional groups based on their roles in cell cycle and/or transcriptional control. This review is centered on CDK9, which is activated by T-type cyclins and cyclin K generating distinct Positive-Transcription Elongation Factors termed P-TEFb. P-TEFb positively regulates transcriptional elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNA pol II), as well as negative elongation factors, which block elongation by RNA pol II shortly after the initiation of transcription. Work over the past few years has led to a dramatic increase in our understanding of how productive transcriptional elongation occurs. This review will briefly describe the mechanisms regulating the activity of T-type cyclin/CDK9 complexes and discuss how these complexes regulate gene expression. For further information, the reader is directed to excellent existing reviews on transcriptional elongation and HIV transcription.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15276198 [PubMed - indexed for MEDLINE]
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7: Plant Mol Biol. 2000 Aug;43(5-6):677-90.
Factors controlling cyclin B expression.
Ito M.
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Japan.
Cyclins control the transition between the phases of the eukaryotic cell cycle as regulatory subunits of the cyclin-dependent kinases (CDKs). Phase-specific activation of the CDK is in part regulated by phase-specific expression of their cyclin component. In most eukaryotic cells including higher plant, B-type cyclin genes are expressed specifically at G2/M phase during the cell cycle. Promoters from yeast, plant and animal B-type cyclin genes are all activated in a cell cycle-regulated manner. In yeast, a transcription factor, Mcm1, in cooperation with an uncloned factor SFF, regulates the cell cycle-dependent promoter activation of mitotic B-type cyclin genes, CLB1 and CLB2. Activity of the human cyclin B1 promoter is regulated by a complex mechanism involving multiple cis-acting elements, none of which are sufficient for G2/M-specific promoter activation. In contrast, plants employ a simple mechanism for cell cycle-regulated promoter activation of B-type cyclin genes. Plant B-type cyclin gene promoters contain a common cis-acting element, called the MSA element, which is necessary and sufficient for the phase-specific promoter activation. MSA-like sequences are also found in the promoters of G2/M-specific genes encoding kinesin-like proteins, suggesting that a defined set of G2/M-specific genes are co-regulated by a common MSA-mediated mechanism in plants. Thus, the molecular mechanisms regulating B-type cyclin gene expression are evolutionarily divergent, and the MSA-mediated mechanism seems to be specific to plants. The consensus sequence of the MSA element resembles the binding sites of animal Myb transcription factors. A set of our data suggest the possibility that plant Myb may have unexpected roles in G2/M by inducing B-type cyclin genes, together with other cell cycle-related genes in plants.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11089869 [PubMed - indexed for MEDLINE]
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8: Adv Clin Path. 1999 Oct;3(4):119-27.
p27 Expression, a cyclin dependent kinase inhibitor in breast carcinoma.
Barbareschi M.
Department of Pathology, S. Chiara Hospital, Trento, Italy. barbareschi@tn.aziendasanitaria.trentino.it.
p27 KIP1 is a cyclin dependent kinase inhibitor, which may act as a potential suppressor gene. Several lines of evidence support the hypothesis that reduced p27 KIP1 expression is related to uncontrolled cell proliferation and tumorigenesis. Low immunohistochemical expression of p27 KIP1 in human neoplasm seems related to tumor progression and poor prognosis. In breast cancer, low p27 is associated with high tumour grade and loss of oestrogen receptor, and it has been suggested that low p27 KIP1 is a powerful and independent prognostic marker of poor clinical outcome. There are however some discrepant results: a few studies, some of which conducted on large series of patients, do not support an independent role of p27 KIP1 as a prognostic marker. We are indeed faced with an intriguing hypothesis, but many more studies are needed to evaluate the real value of p27 KIP1 as a prognostic marker.
Publication Types:
Review
PMID: 10936889 [PubMed - indexed for MEDLINE]
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9: Prog Retin Eye Res. 2000 May;19(3):257-70.
Expression of cyclin-dependent kinase inhibitors during corneal wound repair.
Zieske JD.
Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
During corneal epithelial wound repair, cells migrating to cover the wound area exhibit a drastic reduction in proliferative activity. In contrast, cells distal to the original wound exhibit a greatly enhanced level of proliferative activity. At least 90% of the basal cells in limbal and peripheral corneal epithelia synchronously progress through the cell cycle. The question addressed in this article is whether cyclin-dependent kinase inhibitors play a role in the alterations in proliferative activity seen during corneal wound repair. These inhibitors specifically block cells in the G1-phase of the cell cycle. Two families of cyclin-dependent kinase inhibitors have been identified. The CIP/KIP family includes p21, p27, and p57, while the INK4 family consists of p16. p15. p18. and pI9. At least five of these inhibitors are present in the corneal epithelium. The expression of two of these, p15 and p27. is dramatically altered during wound repair, suggesting that they may be involved in the changes in cell proliferation observed during corneal wound healing.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10749377 [PubMed - indexed for MEDLINE]
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10: J Cell Biochem. 1999 Dec 1;75(3):357-68.
Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression.
Romano G, Kasten M, De Falco G, Micheli P, Khalili K, Giordano A.
Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
HIV-1 gene expression relies upon a complex machinery that is primarily controlled by two viral regulatory proteins, Tat and Rev. Rev is involved in regulating post-transcriptional events of HIV-1 gene expression. The Tat protein transactivates transcription from the HIV-1 5' long terminal repeat (LTR) and acts in synergy with specific cellular factors. Recently, it has been shown that one set of these cellular factors is a protein kinase activity termed TAK (Tat-associated kinase), which activates transcription by hyperphosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II. TAK also enhances transcription of HIV-2, together with the retroviral transactivator, Tat-2. The TAK activity appears to be related to the CTD kinase P-TEFb, which stabilizes transcription elongation of many genes and was originally isolated from Drosophila extracts. Both TAK and P-TEFb contain at least two subunits: the cyclin-dependent kinase, CDK9 (PITALRE), the catalytic subunit, and the regulatory subunit, cyclin T1. CDK9 and cyclin T1 are ubiquitous factors that affects many cellular processes, including cell differentiation and apoptosis. The involvement of TAK in HIV-1 and HIV-2 gene expression is an important aspect in the biology of these two retroviruses, and may lead to the development of novel antiretroviral drugs and/or gene therapy approaches for the treatment of patients with AIDS. Copyright 1999 Wiley-Liss, Inc.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10536359 [PubMed - indexed for MEDLINE]
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11: Kidney Int. 1999 Oct;56(4):1258-61.
Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade.
Terada Y, Inoshita S, Nakashima O, Kuwahara M, Sasaki S, Marumo F.
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan. yterada.med2@med.tmd.ac.jp
Mitogen-activated protein kinases (MAPKs) have been shown to play an important role in transducing extracellular signals into cellular responses. The classic MAPK pathway is commonly activated by growth factors and has been shown to play a crucial role in cell proliferation. Transforming growth factor-beta (TGF-beta)-activating kinase-1 (TAK1) is a novel MAPK kinase kinase that is reported to stimulate the MKK6-p38K pathway. To elucidate the functional roles of the TAK1 pathway, we transfected its constitutive active form (TAKdN) and negative form (TAKK63W) to LLC-PK1 cells. TAKdN stimulated MKK6 phosphorylation and p38K activity and inhibited the percentages of the S and G2/M phases. TAKK63W, the constitutive negative form, reduced TGF-beta-stimulated MKK6 phosphorylation and p38K activity and increased the percentages of the S and G2/M phases. The cyclin D1 protein level is reduced by the TAK1 pathway. We also examined the effects of the TAK1 pathway on cyclin D1 promoter-luciferase assay. The overexpression of TAKdN or p38K inhibited cyclin D1 promoter activity. In contrast, overexpression of the active form of MKK1, the classic MAPK-activator, MKK1 increased cyclin D1 promoter activity and protein level, as well as the percentages of S and G2/M phases.
Publication Types:
Review
PMID: 10504469 [PubMed - indexed for MEDLINE]
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12: Mol Carcinog. 1999 Jan;24(1):1-6.
ras activity and cyclin D1 expression: an essential mechanism of mouse skin tumor development.
Rodriguez-Puebla ML, Robles AI, Conti CJ.
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
ras is a family of small GTP-binding proteins that transduce signals from tyrosine-kinase receptors to the nucleus and thus play a role in the regulation of cell proliferation and differentiation. Several lines of evidence have shown that the cell-cycle machinery, specifically the circuit cyclin D1/cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Point mutations that activate the ras protein and its downstream cascade have been observed in human and experimental tumors. In particular, ras mutations have been well characterized in the mouse skin two-stage carcinogenesis model, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7,12-dimethylbenz[a]anthracene induces a specific point mutation in Ha-ras gene in this model. In the last few years, several studies have shown a correlation between ras activation and alterations in the expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence that cyclin D1 is a critical target of oncogenic ras in mouse skin carcinogenesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor development. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10029404 [PubMed - indexed for MEDLINE]
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13: Genes Chromosomes Cancer. 1998 May;22(1):66-71.
Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression.
Hosokawa Y, Arnold A.
Laboratory of Endocrine Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
The cyclin D1/CCND1 oncogene (PRAD1) is amplified in 15% of primary human breast cancers and overexpressed in 30-50% of breast cancers, suggesting that mechanisms in addition to DNA amplification may lead to deregulated expression of this gene in breast cancer. Cyclin D1 overexpression at a higher frequency than gene amplification is also seen in a variety of other tumors. Cyclin D1 overexpression without amplification could result from a trans-acting regulatory disturbance or could be a consequence of a clonal regulatory mutation in one allele of the gene. We have, therefore, examined whether the overexpression of cyclin D1 mRNA is derived from one parental allele or both alleles in tumor cell lines with or without amplification of the cyclin D1 gene. Eight tumor cell lines, MCF-7, SK-BR-3, ZR-75-1, U-2-OS, SK-LMS-1, DLD1, HCT15, and HT29, out of 20 tumor cells initially examined were found to be heterozygous at the polymorphic NciI site within exon 4 of the cyclin D1 gene. Polymerase chain reaction and NciI digestion (PCR-RFLP) analysis of genomic DNA demonstrated DNA amplification of one allele in the ZR-75-1 cells and HT29 cells and no such imbalance in cyclin D1 gene copy number in the other cells, consistent with Southern blot analyses. Reverse-transcription polymerase chain reaction analysis and NciI digestion (RT-PCR-RFLP) of total cDNA revealed that the overexpressed cyclin D1 mRNA is preferentially derived from the amplified allele in the ZR-75-1 and HT29 cells. In contrast, the other tumor cells overexpressed cyclin D1 mRNA equally from both alleles. This finding strongly suggests that, in breast, sarcoma, and in colon cancer cells with cyclin D1 overexpression and normal gene copy number, elevated levels of cyclin D1 mRNA result from a trans-acting influence on both alleles rather than a clonal somatic mutation or rearrangement in or near a single cyclin D1 gene.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9591636 [PubMed - indexed for MEDLINE]
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14: Biochem Soc Trans. 1997 May;25(2):524-8.
Expression of extracellular matrix molecules, proliferation markers and cyclin-dependent kinase inhibitors in inflamed tissues.
Chilosi M, Doglioni C, Menestrina F, Lestani M, Piazzola E, Benedetti A, Pedron S, Montagna L, Pizzolo G, Mariuzzi GM, Janossy G.
Department of Pathology, University of Verona, Italy.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9191148 [PubMed - indexed for MEDLINE]
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15: Tanpakushitsu Kakusan Koso. 1996 Sep;41(12 Suppl):1725-31.
[Regulation of cyclin E and Cdk2 expression at G1/S transition: post-transcriptional reguration mediated by delta FosB]
[Article in Japanese]
Oda S, Nakabeppu Y.
Cancer Center Kyushu University Hospital, Fukuoka, Japan.
Publication Types:
Review
PMID: 8890629 [PubMed - indexed for MEDLINE]
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16: Nippon Rinsho. 1996 Apr;54(4):1054-9.
[Cyclin D, CDK4 and p16 expression in colorectal cancer]
[Article in Japanese]
Ikeda K, Monden T, Tsujie M, Izawa H, Yamamoto H, Ohnishi T, Ohue M, Sekimoto M, Tomita N, Monden M.
Department of Surgery II, Osaka University Medical School.
G1/S transition of cell cycle is regulated by G1 cyclins/cyclin-dependent kinases (CDKs) and their inhibitors. Cyclin D/CDK4 complex phosphorylates retinoblastoma gene product and p16 inhibits CDK4 in competition with cyclin D. Aberrant expression of these proteins may deregulate cell proliferation and moreover may lead to tumor formation and progression. In this study we examined the expression of cyclin D, CDK4 and p16 in adenoma-carcinoma sequence of colorectum. Immunohistochemical staining revealed that cyclin D was overexpressed in 55 of 66 (83%) adenomas, 8 of 8 (100%) carcinomas in adenoma (CIAs), 26 of 45 (58%) advanced carcinomas and even in hyperplastic mucosa. CDK4 was overexpressed in 0 of 52 (0%) adenomas, 0 of 14 (0%) CIAs and 39 of 45 (87%) advanced carcinomas, but not in hyperplastic mucosa. p16 was overexpressed in only 5 of 52 (10%) adenomas, 10 of 14 (71%) CIA and 59 of 60 (98%) advanced carcinomas, but not in hyperplastic mucosa. And comparative study of CDK4 and p16 showed that CDK4-positive cancer cells also expressed p16. Western blot analysis also revealed that primary regions of advanced colorectal cancer tissues showed 4.61, 3.30, 1.65 and 8.03-fold overexpression on the average in cyclin D1, cyclin D2, CDK4 and p16 respectively. These results indicate that both cyclin D and CDK4 may contribute to phosphorylation of pRB. p16 overexpression would be induced as a brake at G1/S transition through pRB phosphorylation by CDK4 overexpression in advanced colorectal carcinomas.
Publication Types:
English Abstract
Review
PMID: 8920673 [PubMed - indexed for MEDLINE]
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17: Biochem Soc Trans. 1996 Feb;24(1):49-54.
A yeast transcription factor activating G1 cyclin expression has similarity to bacterial signal transduction proteins.
Johnston LH, Morgan BA, Bouquin N.
Division of Yeast Genetics, National Institute for Medical Research, Mill Hill, London, U.K.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 8674720 [PubMed - indexed for MEDLINE]
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18: Prog Cell Cycle Res. 1995;1:115-23.
Cyclin A: function and expression during cell proliferation.
Desdouets C, Sobczak-Thépot J, Murphy M, Bréchot C.
INSERM U370, Paris, France.
Cyclin A is a key regulatory protein which, in mammalian cells, is involved in both S phase and the G2/M transition of the cell cycle through its association with distinct cdks. Several lines of evidence have also implicated cyclin A in carcinogenesis. Our review concentrates on the role of cyclin A in S phase, in the S/G2 transition and in human carcinogenesis; it will also discuss the transcriptional regulation of cyclin A gene.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9552357 [PubMed - indexed for MEDLINE]
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19: Acta Oncol. 1995;34(5):651-6.
Expression and regulation of cyclin genes in breast cancer.
Sutherland RL, Hamilton JA, Sweeney KJ, Watts CK, Musgrove EA.
Cancer Biology Division, Gravan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, N.S.W., Australia.
Cyclins, the regulatory subunits of cyclin-dependent kinases, control passage through key check-points within the cell cycle. Since dysregulated expression and function of cyclins can lead to loss of normal growth control some of these genes are oncogenes. We have studied cyclin gene expression, regulation and function in breast cancers. Induction of cyclin D1 is an early event in mitogenic stimulation of breast cancer cells by growth factors and steroids. Furthermore, inhibition of cyclin D1 expression is an early response to growth inhibition by antioestrogens. Ectopic expression of cyclin D1 in T-47D breast cancer cells demonstrated that cyclin D1 is rate-limiting for progression through G1 phase and is sufficient for growth arrested cells to complete the cell cycle. Since this gene is frequently overexpressed in human breast cancers it may contribute to the development and progression of some breast carcinomas.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7546834 [PubMed - indexed for MEDLINE]
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20: Radiat Res. 1994 Apr;138(1 Suppl):S64-7.
Cyclin expression and G2-phase delay after irradiation.
Bernhard EJ, McKenna WG, Muschel RJ.
Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104.
Many studies have demonstrated the effect of oncogene transfection on the radiation sensitivity of primary rat embryo fibroblasts. Our results indicate that transformation by H-ras plus v-myc oncogenes confers radiation resistance to a much greater extent than transformation by either gene alone. We have further shown that the radioresistant phenotype is accompanied by a prolonged G2-phase delay. This is consistent with the hypothesis that the extent of this delay is an important determinant of radiation sensitivity. The study of cyclin expression during the progression of cells through G2 and M phase after irradiation has also revealed several possible mechanisms for induction of G2-phase arrest. Control of cyclin B levels was seen both at the mRNA level as evidenced by decreased cyclin B mRNA expression after irradiation in the S phase, and at the protein level as demonstrated after irradiation in G2 phase. It remains to be determined how these mechanisms might be differentially regulated in radioresistant and sensitive cells.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8146330 [PubMed - indexed for MEDLINE]
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21: Methods Cell Biol. 1994;41:421-35.
Analysis of DNA content and cyclin protein expression in studies of DNA ploidy, growth fraction, lymphocyte stimulation, and the cell cycle.
Darzynkiewicz Z, Gong J, Traganos F.
Cancer Research Institute, New York Medical College, Valhalla 19595.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 7861973 [PubMed - indexed for MEDLINE]
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22: J Steroid Biochem Mol Biol. 1993 Dec;47(1-6):99-106.
Cyclin gene expression and growth control in normal and neoplastic human breast epithelium.
Sutherland RL, Watts CK, Musgrove EA.
Cancer Biology Division, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia.
Recent advances in defining the molecular mechanisms of cell cycle control in eukaryotes provide a basis for better understanding the hormonal control of cell proliferation in normal and neoplastic breast epithelium. It is now clear that a number of critical steps in cell cycle progression are controlled by families of serine/threonine kinases, the cdks. These kinases are activated by interactions with various cyclin gene products which form the regulatory subunits of the kinase complexes. Several families of cyclins control cell cycle progression in G1 phase, cyclins C, D and E, or in S, G2 and mitosis, cyclins A and B. Recent studies have defined the expression and regulation of cyclin genes in normal breast epithelial cells and in breast cancer cell lines. Following growth arrest of T-47D breast cancer cells by serum deprivation restimulation with insulin results in sequential induction of cyclin genes. Cyclin D1 mRNA increases within 1 h of mitogenic stimulation and is followed by increased expression of cyclins D3 and E in G1 phase, cyclin A in late G1/early S phase and cyclin B1 in G2. Similar results were observed following epidermal growth factor stimulation of normal breast epithelial cells. Other hormones--oestrogens and progestins--and growth factors--insulin-like growth factor-I and basic fibroblast growth factor--with actions in G1 were also investigated for their effects on G1 cyclin gene expression. In all cases there was an excellent correlation between the induction of cyclin D1 mRNA and subsequent entry into S phase. Furthermore, growth inhibition by antioestrogens and concurrent G1 arrest were preceded by an acute decrease in cyclin D1 gene expression. These observations suggest a likely role for cyclin D1 in mediating many of the known hormonal effects on cell proliferation in breast epithelial cells.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8274447 [PubMed - indexed for MEDLINE]
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23: Radiat Res. 1992 Nov;132(2):153-7.
Effects of ionizing radiation on cyclin expression in HeLa cells.
Muschel RJ, Zhang HB, Iliakis G, McKenna WG.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
The levels of cyclin B mRNA and protein rise rapidly in G2 + M phase, and fall at the end of mitosis. The studies described here were initiated to determine the effects of ionizing radiation on the level of cyclin B bearing in mind that the division delay induced by ionizing radiation might be influenced by the expression of cyclin B. After irradiation in S phase, the cyclin B mRNA in HeLa cells was measured as the cells proceeded through the cell cycle. Instead of the usual rise, after irradiation cyclin B mRNA levels remained low during the G2 delay. After irradiation in G2 phase, cyclin B mRNA was readily detectable although at slightly lower levels than in the controls. However, cyclin B protein was markedly decreased in amount.
Publication Types:
Review
PMID: 1438696 [PubMed - indexed for MEDLINE]
Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression.
Tashiro E, Tsuchiya A, Imoto M.
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan.
Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed.
Publication Types:
Review
PMID: 17359287 [PubMed - indexed for MEDLINE]
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2: Pneumonol Alergol Pol. 2005;73(3):297-300.
[Clinical significance of cyclin Dl expression in non-small cell lung cancer]
[Article in Polish]
Dworakowska D.
Klinika Chorób Wewnqtrznych, Endokrynologii i Zaburzeń Hemostazy, AM w Gdańsku. ddw@amg.gda.pl
Lung cancer remains interdisciplinary problem. The genetic alterations in non-small cell lung cancer (NSCLC) are related to tumor suppressor genes and proto-oncogenes. CCND1 gene, coding cyclin DI, in correlation with pRb is involved in regulation of cell cycle arrest in G1 phase. Amplification of CCND1 gene and cyclin D1 over-expression was found in several cancers including head and neck cancers or colorectal cancer, where these alterations were correlated with worse prognosis. The literature addressing the clinical significance of CCND1 gene amplification/expression in NSCLC remains poor and prognostic value of these alterations in that cancer is still controversial.
Publication Types:
English Abstract
Review
PMID: 16989170 [PubMed - indexed for MEDLINE]
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3: Cell Cycle. 2006 Mar;5(5):472-7. Epub 2006 Mar 1.
Do truncated cyclins contribute to aberrant cyclin expression in cancer?
Van Dross R, Browning PJ, Pelling JC.
Department of Pharmacology and Toxicology, Leo Jenkins Cancer Center, East Carolina University, Greenville, North Carolina 27834, USA. vandrossr@ecu.edu
Cyclin overexpression is found in several types of cancer. Genetic events that place cyclin genes under the control of active promoters or that increase cyclin gene copy number account for most instances of cyclin overexpression. New paradigms for aberrant cyclin expression have been suggested by studies showing that truncated cyclins are expressed in specific subsets of cancer. The altered cyclins lack regulatory sequences (compared to the wild-type protein) that modulate their stability, subcellular localization or cdk-associated kinase activity. In this communication, we review the current literature and assess the role of truncated cyclins D, E, A, B, C and virus encoded-cyclin D (K-cyclin) in the development of cancer. We also report the molecular characteristics, expression patterns and if available, prognostic significance of these proteins.
Publication Types:
Review
PMID: 16552186 [PubMed - indexed for MEDLINE]
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4: Cancer Metastasis Rev. 2005 Sep;24(3):383-93.
Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression.
Walker JL, Assoian RK.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Integrins and growth factor receptors coordinately regulate proliferation in nontransformed cells. Coordinate signaling from these receptors controls the activation of the G1 phase cyclin-dependent kinases, largely by regulating levels of cyclin D1 and p27(kip1). Induction of cyclin D1 is one of the best understood examples of an integrin/growth factor receptor-regulated G1 phase target. This review focuses on the integrin-dependent signal transduction events that regulate the expression of cyclin D1 during G1 phase.
Publication Types:
Research Support, N.I.H., Extramural
Review
PMID: 16258726 [PubMed - indexed for MEDLINE]
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5: Clin Otolaryngol Allied Sci. 2004 Dec;29(6):698-704.
Molecular markers in dysplasia of the larynx: expression of cyclin-dependent kinase inhibitors p21, p27 and p53 tumour suppressor gene in predicting cancer risk.
Jeannon JP, Soames JV, Aston V, Stafford FW, Wilson JA.
Department of Otolaryngology Head and Neck Surgery, University of Newcastle-upon-Tyne, Tyne and Wear, UK. jpjeannon@doctors.org.uk
Premalignant conditions affect the larynx. Dysplasia can progress in severity resulting in cancer depending on many clinical, pathological and molecular factors. The purpose of this study was to examine the expression of the p21 and p27 cyclin-dependent kinase inhibitors and p53 tumour suppressor gene in dysplasia of the larynx. A total of 114 cases of untreated dysplasia were selected from the archives of the University of Newcastle. p21, p27 and p53 immunohistochemistry was performed and the cases followed up. Twenty-eight dysplasias (24%) subsequently developed into cancers. Expression of the molecular factors studied was not associated with cancer progression. p53 expression was associated with smoking (P = 0.005). In contrast, grade of dysplasia was significantly associated with cancer risk (odds ratio 6.7; P = 0.0001). The majority (75%) of cancers were detected within 12 months of dysplasia being diagnosed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15533163 [PubMed - indexed for MEDLINE]
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6: Gene. 2004 Aug 4;337:15-23.
Cellular control of gene expression by T-type cyclin/CDK9 complexes.
Garriga J, Graña X.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad St., Philadelphia, PA 19140, USA.
The family of Cyclin-Dependent Kinases (CDKs) can be subdivided into two major functional groups based on their roles in cell cycle and/or transcriptional control. This review is centered on CDK9, which is activated by T-type cyclins and cyclin K generating distinct Positive-Transcription Elongation Factors termed P-TEFb. P-TEFb positively regulates transcriptional elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNA pol II), as well as negative elongation factors, which block elongation by RNA pol II shortly after the initiation of transcription. Work over the past few years has led to a dramatic increase in our understanding of how productive transcriptional elongation occurs. This review will briefly describe the mechanisms regulating the activity of T-type cyclin/CDK9 complexes and discuss how these complexes regulate gene expression. For further information, the reader is directed to excellent existing reviews on transcriptional elongation and HIV transcription.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15276198 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Plant Mol Biol. 2000 Aug;43(5-6):677-90.
Factors controlling cyclin B expression.
Ito M.
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Japan.
Cyclins control the transition between the phases of the eukaryotic cell cycle as regulatory subunits of the cyclin-dependent kinases (CDKs). Phase-specific activation of the CDK is in part regulated by phase-specific expression of their cyclin component. In most eukaryotic cells including higher plant, B-type cyclin genes are expressed specifically at G2/M phase during the cell cycle. Promoters from yeast, plant and animal B-type cyclin genes are all activated in a cell cycle-regulated manner. In yeast, a transcription factor, Mcm1, in cooperation with an uncloned factor SFF, regulates the cell cycle-dependent promoter activation of mitotic B-type cyclin genes, CLB1 and CLB2. Activity of the human cyclin B1 promoter is regulated by a complex mechanism involving multiple cis-acting elements, none of which are sufficient for G2/M-specific promoter activation. In contrast, plants employ a simple mechanism for cell cycle-regulated promoter activation of B-type cyclin genes. Plant B-type cyclin gene promoters contain a common cis-acting element, called the MSA element, which is necessary and sufficient for the phase-specific promoter activation. MSA-like sequences are also found in the promoters of G2/M-specific genes encoding kinesin-like proteins, suggesting that a defined set of G2/M-specific genes are co-regulated by a common MSA-mediated mechanism in plants. Thus, the molecular mechanisms regulating B-type cyclin gene expression are evolutionarily divergent, and the MSA-mediated mechanism seems to be specific to plants. The consensus sequence of the MSA element resembles the binding sites of animal Myb transcription factors. A set of our data suggest the possibility that plant Myb may have unexpected roles in G2/M by inducing B-type cyclin genes, together with other cell cycle-related genes in plants.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11089869 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Adv Clin Path. 1999 Oct;3(4):119-27.
p27 Expression, a cyclin dependent kinase inhibitor in breast carcinoma.
Barbareschi M.
Department of Pathology, S. Chiara Hospital, Trento, Italy. barbareschi@tn.aziendasanitaria.trentino.it.
p27 KIP1 is a cyclin dependent kinase inhibitor, which may act as a potential suppressor gene. Several lines of evidence support the hypothesis that reduced p27 KIP1 expression is related to uncontrolled cell proliferation and tumorigenesis. Low immunohistochemical expression of p27 KIP1 in human neoplasm seems related to tumor progression and poor prognosis. In breast cancer, low p27 is associated with high tumour grade and loss of oestrogen receptor, and it has been suggested that low p27 KIP1 is a powerful and independent prognostic marker of poor clinical outcome. There are however some discrepant results: a few studies, some of which conducted on large series of patients, do not support an independent role of p27 KIP1 as a prognostic marker. We are indeed faced with an intriguing hypothesis, but many more studies are needed to evaluate the real value of p27 KIP1 as a prognostic marker.
Publication Types:
Review
PMID: 10936889 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Prog Retin Eye Res. 2000 May;19(3):257-70.
Expression of cyclin-dependent kinase inhibitors during corneal wound repair.
Zieske JD.
Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
During corneal epithelial wound repair, cells migrating to cover the wound area exhibit a drastic reduction in proliferative activity. In contrast, cells distal to the original wound exhibit a greatly enhanced level of proliferative activity. At least 90% of the basal cells in limbal and peripheral corneal epithelia synchronously progress through the cell cycle. The question addressed in this article is whether cyclin-dependent kinase inhibitors play a role in the alterations in proliferative activity seen during corneal wound repair. These inhibitors specifically block cells in the G1-phase of the cell cycle. Two families of cyclin-dependent kinase inhibitors have been identified. The CIP/KIP family includes p21, p27, and p57, while the INK4 family consists of p16. p15. p18. and pI9. At least five of these inhibitors are present in the corneal epithelium. The expression of two of these, p15 and p27. is dramatically altered during wound repair, suggesting that they may be involved in the changes in cell proliferation observed during corneal wound healing.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10749377 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: J Cell Biochem. 1999 Dec 1;75(3):357-68.
Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression.
Romano G, Kasten M, De Falco G, Micheli P, Khalili K, Giordano A.
Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
HIV-1 gene expression relies upon a complex machinery that is primarily controlled by two viral regulatory proteins, Tat and Rev. Rev is involved in regulating post-transcriptional events of HIV-1 gene expression. The Tat protein transactivates transcription from the HIV-1 5' long terminal repeat (LTR) and acts in synergy with specific cellular factors. Recently, it has been shown that one set of these cellular factors is a protein kinase activity termed TAK (Tat-associated kinase), which activates transcription by hyperphosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II. TAK also enhances transcription of HIV-2, together with the retroviral transactivator, Tat-2. The TAK activity appears to be related to the CTD kinase P-TEFb, which stabilizes transcription elongation of many genes and was originally isolated from Drosophila extracts. Both TAK and P-TEFb contain at least two subunits: the cyclin-dependent kinase, CDK9 (PITALRE), the catalytic subunit, and the regulatory subunit, cyclin T1. CDK9 and cyclin T1 are ubiquitous factors that affects many cellular processes, including cell differentiation and apoptosis. The involvement of TAK in HIV-1 and HIV-2 gene expression is an important aspect in the biology of these two retroviruses, and may lead to the development of novel antiretroviral drugs and/or gene therapy approaches for the treatment of patients with AIDS. Copyright 1999 Wiley-Liss, Inc.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10536359 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Kidney Int. 1999 Oct;56(4):1258-61.
Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade.
Terada Y, Inoshita S, Nakashima O, Kuwahara M, Sasaki S, Marumo F.
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan. yterada.med2@med.tmd.ac.jp
Mitogen-activated protein kinases (MAPKs) have been shown to play an important role in transducing extracellular signals into cellular responses. The classic MAPK pathway is commonly activated by growth factors and has been shown to play a crucial role in cell proliferation. Transforming growth factor-beta (TGF-beta)-activating kinase-1 (TAK1) is a novel MAPK kinase kinase that is reported to stimulate the MKK6-p38K pathway. To elucidate the functional roles of the TAK1 pathway, we transfected its constitutive active form (TAKdN) and negative form (TAKK63W) to LLC-PK1 cells. TAKdN stimulated MKK6 phosphorylation and p38K activity and inhibited the percentages of the S and G2/M phases. TAKK63W, the constitutive negative form, reduced TGF-beta-stimulated MKK6 phosphorylation and p38K activity and increased the percentages of the S and G2/M phases. The cyclin D1 protein level is reduced by the TAK1 pathway. We also examined the effects of the TAK1 pathway on cyclin D1 promoter-luciferase assay. The overexpression of TAKdN or p38K inhibited cyclin D1 promoter activity. In contrast, overexpression of the active form of MKK1, the classic MAPK-activator, MKK1 increased cyclin D1 promoter activity and protein level, as well as the percentages of S and G2/M phases.
Publication Types:
Review
PMID: 10504469 [PubMed - indexed for MEDLINE]
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12: Mol Carcinog. 1999 Jan;24(1):1-6.
ras activity and cyclin D1 expression: an essential mechanism of mouse skin tumor development.
Rodriguez-Puebla ML, Robles AI, Conti CJ.
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
ras is a family of small GTP-binding proteins that transduce signals from tyrosine-kinase receptors to the nucleus and thus play a role in the regulation of cell proliferation and differentiation. Several lines of evidence have shown that the cell-cycle machinery, specifically the circuit cyclin D1/cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Point mutations that activate the ras protein and its downstream cascade have been observed in human and experimental tumors. In particular, ras mutations have been well characterized in the mouse skin two-stage carcinogenesis model, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7,12-dimethylbenz[a]anthracene induces a specific point mutation in Ha-ras gene in this model. In the last few years, several studies have shown a correlation between ras activation and alterations in the expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence that cyclin D1 is a critical target of oncogenic ras in mouse skin carcinogenesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor development. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 10029404 [PubMed - indexed for MEDLINE]
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13: Genes Chromosomes Cancer. 1998 May;22(1):66-71.
Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression.
Hosokawa Y, Arnold A.
Laboratory of Endocrine Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
The cyclin D1/CCND1 oncogene (PRAD1) is amplified in 15% of primary human breast cancers and overexpressed in 30-50% of breast cancers, suggesting that mechanisms in addition to DNA amplification may lead to deregulated expression of this gene in breast cancer. Cyclin D1 overexpression at a higher frequency than gene amplification is also seen in a variety of other tumors. Cyclin D1 overexpression without amplification could result from a trans-acting regulatory disturbance or could be a consequence of a clonal regulatory mutation in one allele of the gene. We have, therefore, examined whether the overexpression of cyclin D1 mRNA is derived from one parental allele or both alleles in tumor cell lines with or without amplification of the cyclin D1 gene. Eight tumor cell lines, MCF-7, SK-BR-3, ZR-75-1, U-2-OS, SK-LMS-1, DLD1, HCT15, and HT29, out of 20 tumor cells initially examined were found to be heterozygous at the polymorphic NciI site within exon 4 of the cyclin D1 gene. Polymerase chain reaction and NciI digestion (PCR-RFLP) analysis of genomic DNA demonstrated DNA amplification of one allele in the ZR-75-1 cells and HT29 cells and no such imbalance in cyclin D1 gene copy number in the other cells, consistent with Southern blot analyses. Reverse-transcription polymerase chain reaction analysis and NciI digestion (RT-PCR-RFLP) of total cDNA revealed that the overexpressed cyclin D1 mRNA is preferentially derived from the amplified allele in the ZR-75-1 and HT29 cells. In contrast, the other tumor cells overexpressed cyclin D1 mRNA equally from both alleles. This finding strongly suggests that, in breast, sarcoma, and in colon cancer cells with cyclin D1 overexpression and normal gene copy number, elevated levels of cyclin D1 mRNA result from a trans-acting influence on both alleles rather than a clonal somatic mutation or rearrangement in or near a single cyclin D1 gene.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9591636 [PubMed - indexed for MEDLINE]
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14: Biochem Soc Trans. 1997 May;25(2):524-8.
Expression of extracellular matrix molecules, proliferation markers and cyclin-dependent kinase inhibitors in inflamed tissues.
Chilosi M, Doglioni C, Menestrina F, Lestani M, Piazzola E, Benedetti A, Pedron S, Montagna L, Pizzolo G, Mariuzzi GM, Janossy G.
Department of Pathology, University of Verona, Italy.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9191148 [PubMed - indexed for MEDLINE]
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15: Tanpakushitsu Kakusan Koso. 1996 Sep;41(12 Suppl):1725-31.
[Regulation of cyclin E and Cdk2 expression at G1/S transition: post-transcriptional reguration mediated by delta FosB]
[Article in Japanese]
Oda S, Nakabeppu Y.
Cancer Center Kyushu University Hospital, Fukuoka, Japan.
Publication Types:
Review
PMID: 8890629 [PubMed - indexed for MEDLINE]
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16: Nippon Rinsho. 1996 Apr;54(4):1054-9.
[Cyclin D, CDK4 and p16 expression in colorectal cancer]
[Article in Japanese]
Ikeda K, Monden T, Tsujie M, Izawa H, Yamamoto H, Ohnishi T, Ohue M, Sekimoto M, Tomita N, Monden M.
Department of Surgery II, Osaka University Medical School.
G1/S transition of cell cycle is regulated by G1 cyclins/cyclin-dependent kinases (CDKs) and their inhibitors. Cyclin D/CDK4 complex phosphorylates retinoblastoma gene product and p16 inhibits CDK4 in competition with cyclin D. Aberrant expression of these proteins may deregulate cell proliferation and moreover may lead to tumor formation and progression. In this study we examined the expression of cyclin D, CDK4 and p16 in adenoma-carcinoma sequence of colorectum. Immunohistochemical staining revealed that cyclin D was overexpressed in 55 of 66 (83%) adenomas, 8 of 8 (100%) carcinomas in adenoma (CIAs), 26 of 45 (58%) advanced carcinomas and even in hyperplastic mucosa. CDK4 was overexpressed in 0 of 52 (0%) adenomas, 0 of 14 (0%) CIAs and 39 of 45 (87%) advanced carcinomas, but not in hyperplastic mucosa. p16 was overexpressed in only 5 of 52 (10%) adenomas, 10 of 14 (71%) CIA and 59 of 60 (98%) advanced carcinomas, but not in hyperplastic mucosa. And comparative study of CDK4 and p16 showed that CDK4-positive cancer cells also expressed p16. Western blot analysis also revealed that primary regions of advanced colorectal cancer tissues showed 4.61, 3.30, 1.65 and 8.03-fold overexpression on the average in cyclin D1, cyclin D2, CDK4 and p16 respectively. These results indicate that both cyclin D and CDK4 may contribute to phosphorylation of pRB. p16 overexpression would be induced as a brake at G1/S transition through pRB phosphorylation by CDK4 overexpression in advanced colorectal carcinomas.
Publication Types:
English Abstract
Review
PMID: 8920673 [PubMed - indexed for MEDLINE]
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17: Biochem Soc Trans. 1996 Feb;24(1):49-54.
A yeast transcription factor activating G1 cyclin expression has similarity to bacterial signal transduction proteins.
Johnston LH, Morgan BA, Bouquin N.
Division of Yeast Genetics, National Institute for Medical Research, Mill Hill, London, U.K.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 8674720 [PubMed - indexed for MEDLINE]
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18: Prog Cell Cycle Res. 1995;1:115-23.
Cyclin A: function and expression during cell proliferation.
Desdouets C, Sobczak-Thépot J, Murphy M, Bréchot C.
INSERM U370, Paris, France.
Cyclin A is a key regulatory protein which, in mammalian cells, is involved in both S phase and the G2/M transition of the cell cycle through its association with distinct cdks. Several lines of evidence have also implicated cyclin A in carcinogenesis. Our review concentrates on the role of cyclin A in S phase, in the S/G2 transition and in human carcinogenesis; it will also discuss the transcriptional regulation of cyclin A gene.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9552357 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Acta Oncol. 1995;34(5):651-6.
Expression and regulation of cyclin genes in breast cancer.
Sutherland RL, Hamilton JA, Sweeney KJ, Watts CK, Musgrove EA.
Cancer Biology Division, Gravan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, N.S.W., Australia.
Cyclins, the regulatory subunits of cyclin-dependent kinases, control passage through key check-points within the cell cycle. Since dysregulated expression and function of cyclins can lead to loss of normal growth control some of these genes are oncogenes. We have studied cyclin gene expression, regulation and function in breast cancers. Induction of cyclin D1 is an early event in mitogenic stimulation of breast cancer cells by growth factors and steroids. Furthermore, inhibition of cyclin D1 expression is an early response to growth inhibition by antioestrogens. Ectopic expression of cyclin D1 in T-47D breast cancer cells demonstrated that cyclin D1 is rate-limiting for progression through G1 phase and is sufficient for growth arrested cells to complete the cell cycle. Since this gene is frequently overexpressed in human breast cancers it may contribute to the development and progression of some breast carcinomas.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7546834 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Radiat Res. 1994 Apr;138(1 Suppl):S64-7.
Cyclin expression and G2-phase delay after irradiation.
Bernhard EJ, McKenna WG, Muschel RJ.
Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104.
Many studies have demonstrated the effect of oncogene transfection on the radiation sensitivity of primary rat embryo fibroblasts. Our results indicate that transformation by H-ras plus v-myc oncogenes confers radiation resistance to a much greater extent than transformation by either gene alone. We have further shown that the radioresistant phenotype is accompanied by a prolonged G2-phase delay. This is consistent with the hypothesis that the extent of this delay is an important determinant of radiation sensitivity. The study of cyclin expression during the progression of cells through G2 and M phase after irradiation has also revealed several possible mechanisms for induction of G2-phase arrest. Control of cyclin B levels was seen both at the mRNA level as evidenced by decreased cyclin B mRNA expression after irradiation in the S phase, and at the protein level as demonstrated after irradiation in G2 phase. It remains to be determined how these mechanisms might be differentially regulated in radioresistant and sensitive cells.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8146330 [PubMed - indexed for MEDLINE]
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21: Methods Cell Biol. 1994;41:421-35.
Analysis of DNA content and cyclin protein expression in studies of DNA ploidy, growth fraction, lymphocyte stimulation, and the cell cycle.
Darzynkiewicz Z, Gong J, Traganos F.
Cancer Research Institute, New York Medical College, Valhalla 19595.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 7861973 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
22: J Steroid Biochem Mol Biol. 1993 Dec;47(1-6):99-106.
Cyclin gene expression and growth control in normal and neoplastic human breast epithelium.
Sutherland RL, Watts CK, Musgrove EA.
Cancer Biology Division, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia.
Recent advances in defining the molecular mechanisms of cell cycle control in eukaryotes provide a basis for better understanding the hormonal control of cell proliferation in normal and neoplastic breast epithelium. It is now clear that a number of critical steps in cell cycle progression are controlled by families of serine/threonine kinases, the cdks. These kinases are activated by interactions with various cyclin gene products which form the regulatory subunits of the kinase complexes. Several families of cyclins control cell cycle progression in G1 phase, cyclins C, D and E, or in S, G2 and mitosis, cyclins A and B. Recent studies have defined the expression and regulation of cyclin genes in normal breast epithelial cells and in breast cancer cell lines. Following growth arrest of T-47D breast cancer cells by serum deprivation restimulation with insulin results in sequential induction of cyclin genes. Cyclin D1 mRNA increases within 1 h of mitogenic stimulation and is followed by increased expression of cyclins D3 and E in G1 phase, cyclin A in late G1/early S phase and cyclin B1 in G2. Similar results were observed following epidermal growth factor stimulation of normal breast epithelial cells. Other hormones--oestrogens and progestins--and growth factors--insulin-like growth factor-I and basic fibroblast growth factor--with actions in G1 were also investigated for their effects on G1 cyclin gene expression. In all cases there was an excellent correlation between the induction of cyclin D1 mRNA and subsequent entry into S phase. Furthermore, growth inhibition by antioestrogens and concurrent G1 arrest were preceded by an acute decrease in cyclin D1 gene expression. These observations suggest a likely role for cyclin D1 in mediating many of the known hormonal effects on cell proliferation in breast epithelial cells.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8274447 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
23: Radiat Res. 1992 Nov;132(2):153-7.
Effects of ionizing radiation on cyclin expression in HeLa cells.
Muschel RJ, Zhang HB, Iliakis G, McKenna WG.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
The levels of cyclin B mRNA and protein rise rapidly in G2 + M phase, and fall at the end of mitosis. The studies described here were initiated to determine the effects of ionizing radiation on the level of cyclin B bearing in mind that the division delay induced by ionizing radiation might be influenced by the expression of cyclin B. After irradiation in S phase, the cyclin B mRNA in HeLa cells was measured as the cells proceeded through the cell cycle. Instead of the usual rise, after irradiation cyclin B mRNA levels remained low during the G2 delay. After irradiation in G2 phase, cyclin B mRNA was readily detectable although at slightly lower levels than in the controls. However, cyclin B protein was markedly decreased in amount.
Publication Types:
Review
PMID: 1438696 [PubMed - indexed for MEDLINE]
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