JBC Invitrogen Ultrasensitive Cytokine Assays

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Originally published In Press as doi:10.1074/jbc.M201336200 on March 27, 2002

J. Biol. Chem., Vol. 277, Issue 22, 19627-19632, May 31, 2002
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Cyclin E Is a Target of WT1 Transcriptional Repression*

David M. LoebDagger , Dorian Korz, Michael Katsnelson, Emily A. Burwell, Alan D. Friedman§, and Saraswati Sukumar

From The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231

WT1 was originally identified as a Wilms' tumor suppressor gene, but it may have oncogenic potential in leukemia and in some solid tumors. WT1 is a transcription factor that has been implicated in the regulation of target genes related to apoptosis, genitourinary differentiation, and cell cycle progression. Because induction of WT1 leads indirectly to increased p21 expression in osteosarcoma cells, we investigated the possibility that other genes involved in the G1/S phase transition might also be WT1 targets. Cyclin E plays a crucial role in the cell cycle by activating cyclin-dependent kinase 2, which phosphorylates Rb, leading to progression from G1 into S phase. We identified several WT1 binding sites in the cyclin E promoter. We demonstrate that WT1 binds to these sites and that in transient transfection assays WT1 represses the cyclin E promoter. This activity is dependent on the presence of a binding site located downstream of the transcription start site. In intact cells, induction of WT1 expression down-regulates cyclin E protein levels. These results provide the first demonstration that WT1 can directly modulate the expression of a gene involved in cell cycle progression.

* This work was supported by Grant R01-CA48943 from the National Institutes of Health (to S. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger A Research Fellow of the Leukemia and Lymphoma Society and recipient of grants from the Lauri Strauss Leukemia Foundation and the Bear Necessities Pediatric Cancer Foundation. To whom correspondence should be addressed: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Division of Pediatric Oncology, Bunting-Blaustein Cancer Research Bldg., Rm. 254, 1650 Orleans St., Baltimore, MD 21231. Tel.: 410-502-7247; Fax: 410-955-8897; E-mail: dmloeb@jhmi.edu.

§ A Scholar of the Leukemia and Lymphoma Society.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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[Abstract] [Full Text] [PDF]


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