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Wnt Expression
Published by Anonymous on 2007/9/30 (1673 reads)
1: Crit Rev Toxicol. 2005 Oct-Nov;35(8-9):727-38.


Mode of action: inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of beta-catenin--developmental effects of valproic acid.

Wiltse J.

US Environmental Protection Agency, Washington, DC, USA. dpatton@ilsi.org

Valproic acid (VPA) has long been known to cause spina bifida, a neural tube defect, and other effects in fetuses of women treated with this drug. Toxicological tests in laboratory mice and rats at human therapeutic doses also show neural tube and other defects. Studies show that VPA alters Wnt signaling in human and animal cells, inducing Wnt-dependent gene expression at doses that cause developmental effects. Structural analogues of VPA that do not have this effect on Wnt signaling do not cause developmental effects. Similarly, Trichostatin A, a compound that mimics VPA in its effects on Wnt gene expression, also causes similar developmental effects. Alteration of Wnt signaling is empirically well supported as the postulated mode of action (MOA) for VPA's developmental effects in animals. VPA causes alteration of Wnt signaling in both human and animal cells systems at the same dose levels. The correspondence of effects on signaling and of effects on development in animals and humans supports the view that alteration of Wnt signaling is a relevant MOA in humans.

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

PMID: 16417040 [PubMed - indexed for MEDLINE]

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2: Dev Growth Differ. 2005 Jun;47(5):273-81.


Regulation of Wnt gene expression.

Tian Q, Jin H, Cui Y, Guo C, Lu X.

Department of Pathology, Oregon Health Sciences University, School of Medicine, Portland, OR 97239, USA. tianq@ohsu.edu

Members of the Wnt gene family play important roles in the regulation of a number of basic developmental processes. Because Wnt is such a potent morphogen, its expression must be controlled tightly and precisely. While many review papers focused on Wnt signaling downstream of the receptor, this review addresses regulations of Wnt itself on several levels, including the transcriptional level, RNA splicing, the post-transcriptional level, the translational level, and the post-translational level. It is these multiple, precise and tight regulations that guarantee that Wnts function correctly both temporally and spatially.

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

PMID: 16026536 [PubMed - indexed for MEDLINE]

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3: Cancer Lett. 2005 Oct 18;228(1-2):117-23.


Wnt-5a gene expression in malignant human neuroblasts.

Blanc E, Goldschneider D, Douc-Rasy S, Bénard J, Raguénez G.

Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Unité Mixte de Recherche 8126, IFR 54, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France.

Neuroblastoma (NB), an embryonal malignancy, poses a major challenge in pediatric oncology for the treatment of disseminated forms. Here, we report the decrease of Wnt-5a gene expression in high-risk NB (HR-NB) as well as in cultured metastatic neuroblasts. Wnt-5a is a member of the Wnt signaling pathway which is mainly associated with patterning decisions in the embryonic nervous system. Moreover, Wnt-5a has been involved in metastatic melanoma progression and invasive ductal breast cancer via adhesion and migration alterations. As retinoic acid (RA) plays a major role in the neural crest induction and differentiation, we showed that RA reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts. While beta-catenin expression remained unchanged, PKC-theta, a protein kinase C isoform, was evidenced to increase and parallel Wnt-5a level. For the first time, the involvement of Wnt-5a through the Wnt/calcium signaling is highlighted in the pathogenesis of a pediatric embryonal malignancy, NB.

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

PMID: 15925444 [PubMed - indexed for MEDLINE]

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4: EMBO Rep. 2000 Jul;1(1):24-8.


Curbing the nuclear activities of beta-catenin. Control over Wnt target gene expression.

Hecht A, Kemler R.

Max-Planck-Institute of Immunobiology, Freiburg, Germany. hecht@immunbio.mpg.de

Wnt molecules control numerous developmental processes by altering specific gene expression patterns, and deregulation of Wnt signaling can lead to cancer. Many Wnt factors employ beta-catenin as a nuclear effector. Upon Wnt stimulation, beta-catenin heterodimerizes with T-cell factor (TCF) DNA-binding proteins to form a transcriptional activator complex. As the activating subunit of this complex, beta-catenin performs dual tasks: it alleviates repression of target gene promoters and subsequently it activates them. Beta-catenin orchestrates these effects by recruiting chromatin modifying cofactors and contacting components of the basal transcription machinery. Although beta-catenin and TCFs are universal activators in Wnt signaling, their target genes display distinct temporal and spatial expression patterns. Apparently, post-translational modifications modulate the interactions between TCFs and beta-catenin or DNA, and certain transcription factors can sequester beta-catenin from TCFs while others synergize with beta-catenin-TCF complexes in a promoter-specific manner. These mechanisms provide points of intersection with other signaling pathways, and contribute to the complexity and specificity of Wnt target gene regulation.

Publication Types:
Review

PMID: 11256619 [PubMed - indexed for MEDLINE]
 

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