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Vol. 18, Issue 3, 755-767, March 2007

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Cell Fate Determination Factor DACH1 Inhibits c-Jun–induced Contact-independent Growth

Kongming Wu^*, Manran Liu^*, Anping Li^*, Howard Donninger, Mahadev Rao, Xuanmao Jiao^*, Michael P. Lisanti^*, Ales Cvekl, Michael Birrer, and Richard G. Pestell^*

*Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057; and Departments of Ophthalmology and Visual Sciences and Molecular Genetics, Albert Einstein College of Medicine, New York, NY 10461

Submitted September 7, 2006; Revised November 20, 2006; Accepted December 5, 2006
Monitoring Editor: Carl-Henrik Heldin

The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun–induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-jun^f1/f1 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli and repressed c-jun target genes (cyclin A, -PAK, and stathmin). DACH1 bound c-Jun and inhibited AP-1 transcriptional activity. c-jun and c-fos were transcriptionally repressed by DACH1, requiring the conserved N-terminal (dac and ski/sno [DS]) domain. c-fos transcriptional repression by DACH1 requires the SRF site of the c-fos promoter. DACH1 inhibited c-Jun transactivation through the domain of c-Jun. DACH1 coprecipitated the histone deacetylase proteins (HDAC1, HDAC2, and NCoR), providing a mechanism by which DACH1 represses c-Jun activity through the conserved domain. An oncogenic v-Jun deleted of the domain was resistant to DACH1 repression. Collectively, these studies demonstrate a novel mechanism by which DACH1 blocks c-Jun-mediated contact-independent growth through repressing the c-Jun domain.

Address correspondence to: Richard G. Pestell (richard.pestell{at}jefferson.edu)

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