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J. Biol. Chem., Vol. 283, Issue 27, 19026-19038, July 4, 2008

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CBFA2T3-ZNF652 Corepressor Complex Regulates Transcription of the E-box Gene HEB^*

Raman Kumar¹, Kelly M. Cheney, Ross McKirdy, Paul M. Neilsen, Renèe B. Schulz, Jaclyn Lee, Juliane Cohen, Grant W. Booker, and David F. Callen

From the Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide and Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia 5000, Australia and the School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia

Transcriptional repression plays a critical role in development and homeostasis. The ETO family represents a group of highly conserved and ubiquitously expressed transcriptional regulatory proteins that are components of a diverse range of multiprotein repressor complexes. ETO proteins function as transcriptional repressors by interacting with a number of transcription factors that bind to their cognate consensus DNA binding sequences within the promoters of target genes. We previously reported that the classical C₂H₂ zinc finger DNA-binding protein, ZNF652, specifically and functionally interacts with the ETO protein CBFA2T3 and has a role in the suppression of breast oncogenesis. Here we report the identification and validation of the ZNF652 consensus DNA binding sequence. Our results show that the E-box gene HEB is a direct target of CBFA2T3-ZNF652-mediated transcriptional repression. The CBFA2T3-ZNF652 complex regulates HEB expression by binding to a single ZNF652 response element located within the promoter sequence of HEB. This study also shows that the NHR3 and NHR4 domains of CBFA2T3 interact with a conserved proline-rich region located within the C terminus of ZNF652. Our results, together with previous reports, indicate that HEB has a complex relationship with CBFA2T3; CBFA2T3 interacts with ZNF652 to repress HEB expression, and in addition CBFA2T3 interacts with the HEB protein to inhibit its activator function. These findings suggest that CBFA2T3-ZNF652-mediated HEB regulation may play an important role in hematopoiesis and myogenesis.

Received for publication, November 7, 2007 , and in revised form, April 4, 2008.

^* This work was supported by Grant 207703 from the National Health and Medical Research Council of Australia, the Youth Breast Cancer Association, and the Susan G. Komen Breast Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Hanson Inst., IMVS, Frome Rd., Adelaide, South Australia 5000, Australia. Fax: 61-8-8222-3217; E-mail: raman.sharma{at}imvs.sa.gov.au.

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