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Transforming Growth Factor-ß1 Recruits Histone Deacetylase 1 to a p130 Repressor Complex in Transgenic Mice in Vivo¹

The Albert Einstein Cancer Center, Departments of Developmental and Molecular Biology [B. B., M. F., A. I., R. G. P.], Medicine [A. I., R. G. P.], and Neurology [A. I.], Albert Einstein College of Medicine, Bronx, New York 10461, and Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255 [V. M. F., S. S. T.]

Transforming growth factor (TGF)-ß1 functions as a tumor suppressor in vivo. Using transgenic mice, we show that hepatic TGF-ß1 overexpression inhibits abundance of the cyclin-dependent kinase activating tyrosine phosphatase cdc25A protein. The reduction in cdc25A protein levels was associated with increased binding of histone deacetylase 1 to p130 in the hepatic extracts. In cultured cells, HDAC1/p130 overexpression inhibited activity of the cdc25A promoter through an E2F site. TGF-ß1 treatment enhanced p130 binding to the cdc25A promoter E2F site assessed in chromatin immunoprecipitation assays. Hepatic proliferation induced by partial hepatectomy was associated with a decrease in the amount of HDAC1 bound to p130, without a significant decrease in p130 abundance, suggesting that HDAC1 binding to p130 may be regulated by proliferative stimuli. The induction of cdc25A abundance induced by partial hepatectomy correlated with the induction of DNA synthesis. These studies suggest that TGF-ß1 may enhance HDAC1 binding to p130 in vivo, thereby inhibiting cdc25A gene expression. TGF-ß1 regulation of HDAC1/pocket protein associations may provide a link between chromatin remodeling proteins and cdk inhibition through induction of cdc25A in vivo.

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