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NCI CANCERLIT^® Search: Wilms' Tumor Gene (WT1) - April 2002

National Cancer Institute^®
Last Modified: April 1, 2002

Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation.

Advances in the molecular basis of renal neoplasia.

The Wilms' tumor gene Wt1 is required for normal development of the retina.

Table of Contents

1
UI - 8896454
AU - Ye Y; Raychaudhuri B; Gurney A; Campbell CE; Williams BR
TI - Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation.
SO - EMBO J 1996 Oct 15;15(20):5606-15
AD - Department of Cancer Biology, Cleveland Clinic Foundation, OH 44195-5001, USA.
Phosphorylation is one of the major post-translational mechanisms by which the activity of transcription factors is regulated. We have investigated the role of phosphorylation in the regulation of nucleic acid binding activity and the nuclear translocation of WT1. Two recombinant WT1 proteins containing the DNA binding domain with or without a three amino acid (KTS) insertion (WT1ZF + KTS and WT1ZF - KTS) were strongly phosphorylated by protein kinase A (PKA) and protein kinase C (PKC) in vitro. Both PKA and PKC phosphorylation inhibited the ability of WT1ZF + KTS or WT1ZF - KTS to bind to a sequence derived from the WT1 promoter region in gel mobility shift assays. The binding of WT1ZF - KTS to an EGR1 consensus binding site was also inhibited by prior PKA and PKC phosphorylation. We also demonstrate the RNA binding activity of WT1, but this was not altered by phosphorylation. PKA activation by dibutyryl cAMP in WT1-transfected cells resulted in the reversal of WT1 suppression of a reporter construct. Although WT1 protein is predominantly localized to the nucleus, this expression pattern is altered upon PKA activation, resulting in the cytoplasmic retention of WT1. Accordingly, phosphorylation may play a role in modulating the transcriptional regulatory activity of WT1 through interference with nuclear translocation, as well as by inhibition of WT1 DNA binding.

2
UI - 10456263
AU - Cohen HT
TI - Advances in the molecular basis of renal neoplasia.
SO - Curr Opin Nephrol Hypertens 1999 May;8(3):325-31
AD - Department of Medicine, Boston University Medical Center, MA 02118, USA. htcohen@bu.edu
The past 2 years have provided exciting progress in elucidating the molecular basis of renal cancer. Work on the von Hippel-Lindau tumor suppressor, pVHL, in clear-cell renal cancer is already suggesting new potential therapies, and should have important implications in the pathogenesis of renal cystic disease and tumor angiogenesis. In addition, study of the Wilms' tumor suppressor, WT1, is revealing much about the pathogenesis of Wilms' tumor, urogenital development, and glomerular podocyte biology. c-met, the gene encoding the hepatocyte growth factor receptor, has recently been identified as a causative gene for hereditary papillary renal cancer. This review will highlight these and other new molecular advances in the renal cancer field.

3
UI - 11889045
AU - Wagner KD; Wagner N; Vidal VP; Schley G; Wilhelm D; Schedl A; Englert C;
TI - Scholz H The Wilms' tumor gene Wt1 is required for normal development of the retina.
SO - EMBO J 2002 Mar 15;21(6):1398-405
AD - Johannes-Muller-Institut fur Physiologie, Medizinische Fakultat Charite, Humboldt-Universitat, Berlin, Germany.
The Wilms' tumor gene Wt1 is known for its important functions during genitourinary and mesothelial formation. Here we show that Wt1 is necessary for neuronal development in the vertebrate retina. Mouse embryos with targeted disruption of Wt1 exhibit remarkably thinner retinas than age-matched wild-type animals. A large fraction of retinal ganglion cells is lost by apoptosis, and the growth of optic nerve fibers is severely disturbed. Strikingly, expression of the class IV POU-domain transcription factor Pou4f2 (formerly Brn-3b), which is critical for the survival of most retinal ganglion cells, is lost in Wt1(-/-) retinas. Forced expression of Wt1 in cultured cells causes an up-regulation of Pou4f2 mRNA. Moreover, the Wt1(-KTS) splice variant can activate a reporter construct carrying 5'-regulatory sequences of the human POU4F2. The lack of Pou4f2 and the ocular defects in Wt1(-/-) embryos are rescued by transgenic expression of a 280 kb yeast artificial chromosome carrying the human WT1 gene. Taken together, our findings demonstrate a continuous requirement for Wt1 in normal retina formation with a critical role in Pou4f2-dependent ganglion cell differentiation.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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