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PMID: 7588596 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.

The EMBO journal ·Vol. 14 ·No. 19 ·1995-10-02 ·Pages 4662-75

Englert C, Hou X, Maheswaran S, Bennett P, Ngwu C, Re GG, Garvin AJ, Rosner MR, Haber DA

Abstract

The Wilms tumor suppressor gene WT1 encodes a developmentally regulated transcription factor that is mutated in a subset of embryonal tumors. To test its functional properties, we developed osteosarcoma cell lines expressing WT1 under an inducible tetracycline-regulated promoter. Induction of WT1 resulted in programmed cell death. This effect, which was differentially mediated by the alternative splicing variants of WT1, was independent of p53. WT1-mediated apoptosis was associated with reduced synthesis of the epidermal growth factor receptor (EGFR), but not of other postulated WT1-target genes, and it was abrogated by constitutive expression of EGFR. WT1 repressed transcription from the EGFR promoter, binding to two TC-rich repeat sequences. In the developing kidney, EGFR expression in renal precursor cells declined with the onset of WT1 expression. Repression of EGFR and induction of apoptosis by mechanism that may contribute to its critical role in normal kidney development and to the immortalization of tumor cells with inactivated WT1 alleles.

MeSH Terms
Alternative Splicing Animals Animals, Newborn Apoptosis/physiology Base Sequence DNA, Neoplasm/metabolism DNA-Binding Proteins/genetics,metabolism,physiology Early Growth Response Protein 1 ErbB Receptors/biosynthesis Genes, Wilms Tumor/genetics Humans Immediate-Early Proteins Kidney/embryology,metabolism Molecular Sequence Data Osteosarcoma Promoter Regions, Genetic/genetics Rats Transcription Factors/genetics,metabolism,physiology Transcription, Genetic Transfection Tumor Cells, Cultured Tumor Suppressor Protein p53/physiology WT1 Proteins
Chemicals
DNA, Neoplasm DNA-Binding Proteins EGR1 protein, human Early Growth Response Protein 1 Egr1 protein, rat Immediate-Early Proteins Transcription Factors Tumor Suppressor Protein p53 WT1 Proteins ErbB Receptors
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Englert C
Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Hou X
Maheswaran S
Bennett P
Ngwu C
Re G G
Garvin A J
Rosner M R
Haber D A
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1995-10-02
Pages
4662-75
Language
English
Region
England
NLM ID
8208664
PMCID
PMC394563
Subset
IM
Grants
NCI NIH HHS · CA 37887 · United States
NCI NIH HHS · CA35541 · United States
NCI NIH HHS · CA58596 · United States
External Links
PubMed source PMC Full Text View journal details
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