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Induction of p21 by the Wilms' Tumor Suppressor Gene WT1¹

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129 [C. E., S. M., D. A. H.]; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29325 [A. J. G.]; and Children's Hospital and Harvard Medical School, Boston, Massachusetts 02114 [J. K.]

WT1 encodes a zinc finger transcription factor that is expressed in the developing kidney and the inactivation of which leads to Wilms' tumor, a pediatric kidney cancer. We have recently shown that inducible expression of WT1 in osteosarcoma cells triggers programmed cell death, an effect that is associated with transcriptional repression of the endogenous epidermal growth factor receptor. We now show that WT1-mediated apoptosis is preceded by induction of the cyclin-dependent kinase inhibitor p21, associated with G₁ phase arrest. This effect is only demonstrated by WT1 isoforms with an intact DNA binding domain, and it is associated with increased expression of endogenous p21 mRNA. WT1-mediated induction of p21 is independent of p53, another tumor suppressor gene known to regulate p21 expression. In the kidney, p21 is expressed in differentiating glomerular podocytes along with WT1. We conclude that induction of p21 expression may contribute to WT1-dependent differentiation pathways in the kidney and potentially to the function of WT1 as a tumor suppressor gene.

¹ This work was supported by NIH Grants CA58596 (to D. A. H.) and CA37887 (to A. J. G.) and by a grant from the Deutsche Forschungsgemeinschaft (to C. E.).

² Current address: Institut fur Genetik, Forschungszentrum Karlsruhe, Karlsruhe, D76021, Germany.

³ To whom requests for reprints should be addressed, at Massachusetts General Hospital Cancer Center, CNY 7, Building 149, 13th Street, Charlestown, MA 02129. Phone: (617) 726-7805; Fax: (617) 726-5637; E-mail: Haber@helix.mgh.harvard.edu.

Received 1/ 2/97. Accepted 3/ 8/97.

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