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c-Myc Function
Published by Anonymous on 2007/9/30 (1802 reads)
1: Cell Cycle. 2007 Jun;6(11):1324-8. Epub 2007 Jun 14.


The function and regulation of the JARID1 family of histone H3 lysine 4 demethylases: the Myc connection.

Secombe J, Eisenman RN.

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.

Epigenetic regulation of transcription refers to reversible, heritable changes in gene expression that occur in the absence of changes in DNA sequence. A major epigenetic mechanism involves the covalent modification of nucleosomal histones to create binding sites for transcriptional regulators and chromatin remodeling complexes that mediate activation or repression of transcription. While it has been known for a number of years that many histone modifications are reversible, it has only recently been shown that methyl groups are enzymatically removed from lysine residues. Here we discuss the recent characterization of a new class of demethylase enzyme, the JARID1 family, which catalyzes the removal of methyl groups from lysine 4 of histone H3. We summarize recent findings regarding the function of this family of proteins, focusing on our characterization of Little imaginal discs (Lid), the sole JARID1 family protein in Drosophila, which is rate-limiting for Myc-induced cell growth. Finally, we propose models to explain the role of Lid in Myc-mediated growth and discuss the relevance of these findings to human disease and tumor formation.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

PMID: 17568193 [PubMed - indexed for MEDLINE]

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2: Semin Cancer Biol. 2006 Aug;16(4):288-302. Epub 2006 Aug 17.


Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function.

Hann SR.

Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. steve.hann@vanderbilt.edu

The Myc proteins play a central role in cellular proliferation, differentiation, apoptosis and tumorigenesis. Although it is clear that multiple molecular mechanisms mediate these functions, it is unclear how individual mechanisms contribute and if different mechanisms work in concert or separately in mediating the diverse biological functions of c-Myc. Similarly, the role of post-translational modifications in regulating c-Myc molecular and biological properties has remained uncertain, despite over 20 years of research. In particular, phosphorylation of the N-terminal transcriptional regulatory domain has been shown to have a variety of consequences ranging from dramatic effects on apoptosis, tumorigenesis and c-Myc proteolysis to negligible effects on cellular transformation and transcriptional activity. This review attempts to provide a comprehensive and critical evaluation of the accumulated evidence to address the complex and controversial issues surrounding the role of post-translational modifications in c-Myc function, focusing on phosphorylation and ubiquitination of the N-terminal transcriptional regulatory domain. An overall model emerges that suggests phosphorylation and ubiquitination play critical roles in cell cycle progression, cell growth, apoptosis and tumorigenesis that are mediated by phosphorylation-dependent transcriptional activation of distinct sets of target genes and synchronized proteolysis.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 16938463 [PubMed - indexed for MEDLINE]

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3: Curr Top Microbiol Immunol. 2006;302:63-122.


The Mad side of the Max network: antagonizing the function of Myc and more.

Rottmann S, Lüscher B.

Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Klinikum der RWTH, Pauwelsstrasse 30, 52074 Aachen, Germany.

A significant body of evidence has been accumulated that demonstrates decisive roles of members of the Myc/Max/Mad network in the control of various aspects of cell behavior, including proliferation, differentiation, and apoptosis. The components of this network serve as transcriptional regulators. Mad family members, including Mad1, Mxi1, Mad3, Mad4, Mnt, and Mga, function in part as antagonists of Myc oncoproteins. At the molecular level this antagonism is reflected by the different cofactor/chromatin remodeling complexes that are recruited by Myc and Mad family members. One important function of the latter is their ability to repress gene transcription. In this review we summarize the current view of how this repression is achieved and what the consequences of Mad action are for cell behavior. In addition, we point out some of the many aspects that have not been clarified and thus leave us with a rather incomplete picture of the functions, both molecular and at the cellular level, of Mad family members.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16620026 [PubMed - indexed for MEDLINE]

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4: Oncogene. 2001 Sep 10;20(40):5595-610.


Translocations involving c-myc and c-myc function.

Boxer LM, Dang CV.

Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California CA 94305, USA.

c-MYC is the prototype for oncogene activation by chromosomal translocation. In contrast to the tightly regulated expression of c-myc in normal cells, c-myc is frequently deregulated in human cancers. Herein, aspects of c-myc gene activation and the function of the c-Myc protein are reviewed. The c-myc gene produces an oncogenic transcription factor that affects diverse cellular processes involved in cell growth, cell proliferation, apoptosis and cellular metabolism. Complete removal of c-myc results in slowed cell growth and proliferation, suggesting that while c-myc is not required for cell proliferation, it acts as an integrator and accelerator of cellular metabolism and proliferation.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 11607812 [PubMed - indexed for MEDLINE]

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5: Gene. 2001 Oct 17;277(1-2):1-14.


Function and regulation of the transcription factors of the Myc/Max/Mad network.

Lüscher B.

Abt. Biochemie und Molekularbiologie, Institut für Biochemie, Universitätsklinikum der RWTH, Pauwelstrasse 30, 52057 Aachen, Germany. luescher@rwth-aachen.de

The members of the Myc/Max/Mad network function as transcriptional regulators. Substantial evidence has been accumulated over the last years that support the model that Myc/Max/Mad proteins affect different aspects of cell behavior, including proliferation, differentiation, and apoptosis, by modulating distinct target genes. The unbalanced expression of these genes, e.g. in response to deregulated Myc expression, is most likely an important aspect of Myc's ability to stimulate tumor formation. Myc and Mad proteins affect target gene expression by recruiting chromatin remodeling activities. In particular Myc interacts with a SWI/SNF-like complex that may contain ATPase activity. In addition Myc binds to TRRAP complexes that possess histone acetyl transferase activity. Mad proteins, that antagonize Myc function, recruit an mSin3 repressor complex with histone deacetylase activity. Thus the antagonism of Myc and Mad proteins is explained at the molecular level by the recruitment of opposing chromatin remodeling activities.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 11602341 [PubMed - indexed for MEDLINE]

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6: Biochim Biophys Acta. 2001 Mar 21;1471(3):M135-45.


Function of the c-Myc oncoprotein in chromatin remodeling and transcription.

Amati B, Frank SR, Donjerkovic D, Taubert S.

Department of Oncology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304, USA. bruno.amati@dnax.org

Deregulated expression of the c-myc proto-oncogene contributes to malignant progression of a variety of tumors. The c-Myc protein (or Myc) is a transcription factor that positively or negatively regulates expression of distinct sets of target genes. Transcriptional activation by Myc is mediated through dimerization with Max and binding to the DNA consensus sequence CA(C/T)GTG (the E-box). Transcriptional inhibition is mediated through distinct DNA elements, and may be due to functional interference with factors that transactivate via these sequences. We review here our current knowledge on these transcriptional activities of Myc and their relationship to its biological function. The findings that Myc interacts with subunits of histone acetyl-transferase (HAT) complexes and of the ATP-dependent chromatin remodeling complex, SWI/SNF, suggest that localized changes in chromatin structure may mediate Myc function. We present a working hypothesis for the concerted action of HAT and SWI/SNF complexes in Myc-activated transcription and argue that this model should prompt re-thinking of the experimental strategies and criteria used to identify Myc target genes.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 11250069 [PubMed - indexed for MEDLINE]

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7: Exp Cell Res. 1999 Nov 25;253(1):63-77.


Function of the c-Myc oncogenic transcription factor.

Dang CV, Resar LM, Emison E, Kim S, Li Q, Prescott JE, Wonsey D, Zeller K.

Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA. cvdang@welch.jhu.edu

The c-myc gene and the expression of the c-Myc protein are frequently altered in human cancers. The c-myc gene encodes the transcription factor c-Myc, which heterodimerizes with a partner protein, termed Max, to regulate gene expression. Max also heterodimerizes with the Mad family of proteins to repress transcription, antagonize c-Myc, and promote cellular differentiation. The constitutive activation of c-myc expression is key to the genesis of many cancers, and hence the understanding of c-Myc function depends on our understanding of its target genes. In this review, we attempt to place the putative target genes of c-Myc in the context of c-Myc-mediated phenotypes. From this perspective, c-Myc emerges as an oncogenic transcription factor that integrates the cell cycle machinery with cell adhesion, cellular metabolism, and the apoptotic pathways. Copyright 1999 Academic Press.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 10579912 [PubMed - indexed for MEDLINE]

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8: Oncogene. 1999 May 13;18(19):2955-66.


The basic region/helix-loop-helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation.

Lüscher B, Larsson LG.

Institut für Molekularbiologie, Medizinische Hochschule Hannover, Germany. blue@ifm.mh-hannover.de

A large body of evidence has been accumulated that demonstrates dominant effects of Myc proto-oncoproteins on different aspects of cellular growth. Myc is one of the few proteins that is sufficient to drive resting cells into the cell cycle and promote DNA synthesis. In line with this finding is that the constitutive expression of Myc in cells blocks their differentiation. These growth stimulating properties are most likely responsible for Myc's ability to initiate and promote tumor formation. Interestingly Myc can also sensitize cells to apoptosis, suggesting that this protein is part of a life-and-death switch. Molecularly Myc functions as a transcriptional regulator that needs to heterodimerize with Max to exert the biological activities described above and to regulate gene transcription. Myc and Max are just two members of a growing family of proteins referred to as the Myc/Max/Mad network. A hallmark of these proteins is that they possess a C-terminal basic region/helix-loop-helix/leucine zipper domain (bHLHZip). The bHLHZip domain specifies dimerization within the network and determines sequence specific DNA binding. Importantly this domain together with the N-terminal transactivation domain is essential for Myc biology. Here we have summarized the structural, functional, and regulatory aspects of the bHLHZip domain of Myc proteins.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10378692 [PubMed - indexed for MEDLINE]

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9: Curr Top Microbiol Immunol. 1997;224:149-58.


Regulated expression and function of the c-Myc antagonist, Mad1, during a molecular switch from proliferation to differentiation.

Cultraro CM, Bino T, Segal S.

NCI-Navy Medical Oncology Branch, National Cancer Institute, NIH, Bethesds, MD, USA.

Publication Types:
Review

PMID: 9308238 [PubMed - indexed for MEDLINE]

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10: Curr Top Microbiol Immunol. 1995;194:273-82.


Association with c-Myc: an alternated mechanism for c-Myc function.

Shrivastava A, Calame K.

Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032.

Publication Types:
Review

PMID: 7895499 [PubMed - indexed for MEDLINE]

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11: Semin Cancer Biol. 1994 Feb;5(1):21-36.


Use of transgenic mice to study myc family gene function in normal mammalian development and in cancer.

Morgenbesser SD, DePinho RA.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.

The myc family of cellular oncogenes (c-, N- and L-myc) encode for nuclear phosphoproteins that appear to regulate cellular proliferation and differentiation during normal vertebrate development. In addition, their overexpression has been correlated with malignant transformation and apoptotic cell death. The transgenic mouse technology has been utilized to study the unique and overlapping functions of the myc family in these cellular processes in the context of the developing animal. These studies suggest that Myc oncoproteins serve important roles during normal development and that their deregulated expression is causal in the development of many malignancies. Furthermore, these experiments have provided insight into the cell type specific activities of each gene and into the unique and overlapping roles of the genes during normal development.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8186385 [PubMed - indexed for MEDLINE]

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12: Clin Chim Acta. 1993 Jul 30;217(1):57-62.


Myc amplification: regulation of myc function.

Koskinen PJ, Mäkelä TP, Västrik I, Alitalo K.

Department of Virology, University of Helsinki, Finland.

The myc oncogenes have been implicated in the control of cell proliferation in both normal and neoplastic cells. There is increasing evidence that Myc proteins function as transcriptional regulators of other genes apparently involved in the control of cell proliferation. The effects of Myc on both gene expression and cell growth are differentially regulated by the recently described Max and delta Max proteins that can either cooperate or compete with Myc for sequence-specific DNA binding.

Publication Types:
Review

PMID: 8222283 [PubMed - indexed for MEDLINE]

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13: FASEB J. 1992 Sep;6(12):3065-72.


Function of the c-Myc oncoprotein.

Kato GJ, Dang CV.

Department of Pediatric, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

The c-Myc protein, the product of the c-myc proto-oncogene, is a nuclear phosphoprotein with DNA binding properties. Deregulated c-myc expression participates in the development of experimentally induced tumors, and its expression appears to be abnormal in many naturally occurring malignancies. Although the precise molecular mechanism of c-Myc activity in oncogenesis and in normal cell proliferation is unknown, recent advances have uncovered a series of molecular and cellular properties of c-Myc. These properties include nuclear localization, transcriptional activation, oligomerization nonspecific and specific DNA binding. Recently, the c-Myc protein was found to heterodimerize with Max, a protein that cooperates with c-Myc to bind specifically to a core DNA sequence, CAC(G/A)TG. These characteristics suggest that c-Myc participates in the regulation of gene transcription in normal and neoplastic cells.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 1521738 [PubMed - indexed for MEDLINE]

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14: Curr Opin Genet Dev. 1992 Apr;2(2):227-35.


Myc and Max function as a nucleoprotein complex.

Blackwood EM, Kretzner L, Eisenman RN.

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.

The Myc family of oncoproteins are thought to regulate proliferation and differentiation in a wide variety of cell types. Recent studies show that Myc proteins form sequence-specific DNA-binding complexes with Max, a new member of the helix-loop-helix leucine zipper protein class. The properties of the Myc-Max complex suggest a mechanism for Myc's function in both normal and neoplastic cell behavior.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 1638116 [PubMed - indexed for MEDLINE]

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15: Annu Rev Biochem. 1992;61:809-60.


myc function and regulation.

Marcu KB, Bossone SA, Patel AJ.

Department of Biochemistry and Cell Biology, State University of New York, Stony Brook 11794.

Publication Types:
Review

PMID: 1497324 [PubMed - indexed for MEDLINE]

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16: Biochim Biophys Acta. 1991 Dec 10;1072(2-3):103-13.


c-myc oncoprotein function.

Dang CV.

Department of Medicine, Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD.

Genetic alterations of the c-myc locus in various malignancies and the ability of c-myc to transform cultured cells and induce tumors in transgenic animals attest to its central role in many neoplasms. By dissecting the c-Myc protein, a number of critical functional domains of c-Myc have been identified and characterized; these findings suggest a model for c-Myc function and intracellular activity (Fig. 4). c-Myc is synthesized in the cytoplasm and undergoes oligomerization another protein such as Max. Its nuclear localization signal allows c-Myc to be targeted to and retained in the nucleus, where the protein seeks out and binds to specific DNA sites, perhaps facilitated by c-Myc's ability to bind non-specifically to DNA. Once bound to specific DNA sequences, c-Myc then activates or inhibits transcription of a number of target genes, with consequent alterations in cell growth and differentiation. Continued studies of c-Myc and its partner Max should further elucidate the mechanisms by which c-Myc can contribute both to the regulation of normal cell growth and the alteration in that regulation in neoplasia.

Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 1751543 [PubMed - indexed for MEDLINE]

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17: Crit Rev Oncog. 1990;2(1):75-95.


Expression and function of myc family genes.

Zimmerman K, Alt FW.

Department of Biochemistry, Columbia University, New York, New York 10032.

The myc family of nuclear oncogenes contains three well-characterized members, c-myc, N-myc, and L-myc. These genes encode related but distinct nuclear proteins that can contribute to tumorigenic conversion both in vitro and in vivo. However, each gene displays a unique activation pattern in spontaneously arising tumors, a pattern that partially reflects the unique expression pattern of each gene during normal development. Although the specific function of myc family genes has not been determined, changes in myc gene expression accompany in vitro exposure to growth and differentiation stimuli, suggesting an important role in these cellular processes. In addition, the homologies shared among myc genes and two groups of DNA binding, transcriptional regulatory proteins suggests a role in regulating gene expression. This review describes the similar and unique properties of individual members of the myc gene family with respect to their expression and potential role during normal development and in the tumorigenic conversion process.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2091750 [PubMed - indexed for MEDLINE]

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18: IARC Sci Publ. 1988;(92):185-8.


A hypothesis for the function of proteins of the myc-family.

Taya Y.

Biology Division, National Cancer Center Research Institute, Tokyo, Japan.

Publication Types:
Comparative Study
Review

PMID: 3069728 [PubMed - indexed for MEDLINE]
 

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