Transforming growth factor-beta 1 recruits histone deacetylase 1 to a p130repressor complex in transgenic mice in vivo

Transforming growth factor (TGF)-beta 1 functions as a tumor suppressor in vivo. Using transgenic mice, we show that hepatic TGF-beta 1 overexpression inhibits abundance of the cyclin-dependent kinase activating tyrosine phos phatase cdc25A protein. The reduction in cdc25A protein levels was associat ed with increased binding of histone deacetylase 1 to p130 in the hepatic e xtracts, In cultured cells, HDAC1/p130 overexpression inhibited activity of the cdc25A promoter through an E2F site. TGF-beta 1 treatment enhanced p13 0 binding to the cdc25A promoter E2F site assessed in chromatin immunopreci pitation assays. Hepatic proliferation induced by partial hepatectomy was a ssociated with a decrease in the amount of HDAC1 bound to p130, without a s ignificant decrease in p130 abundance, suggesting that HDAC1 binding to p13 0 may be regulated by proliferative stimuli. The induction of cdc25A abunda nce induced by partial hepatectomy correlated with the induction of DNA syn thesis. These studies suggest that TGF-beta 1 may enhance HDAC1 binding to p130 irt vivo, thereby inhibiting cdc25A gene expression, TGF-beta 1 regula tion of HDAC1/pocket protein associations may provide a link between chroma tin remodeling proteins and cdk inhibition through induction of cdc25A in v ivo.