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Transforming growth factor-beta1 recruits histone deacetylase 1 to a p130 repressor complex in transgenic mice in
B Bouzahzah1, M Fu, A Iavarone
1The Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Transforming growth factor (TGF)-beta1 functions as a tumor suppressor in vivo. Using transgenic mice, we show that hepatic TGF-beta1 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-beta1 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-beta1 may enhance HDAC1 binding to p130 in vivo, thereby inhibiting cdc25A gene expression. TGF-beta1 regulation of HDAC1/pocket protein associations may provide a link between chromatin remodeling proteins and cdk inhibition through induction of cdc25A in vivo.
Insights
Transforming growth factor-beta1 (TGF-β1) suppresses tumors by reducing cdc25A protein. This involves increased binding of histone deacetylase 1 (HDAC1) to p130, inhibiting cdc25A gene expression.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Transforming growth factor-beta1 (TGF-β1) is recognized for its tumor suppressor functions.
- Cyclin-dependent kinase (CDK) regulators play critical roles in cell cycle control and cancer development.
- Histone deacetylases (HDACs) and pocket proteins are involved in gene regulation and cellular processes.
Purpose of the Study:
- To investigate the mechanism by which TGF-β1 inhibits cdc25A protein abundance in vivo.
- To explore the role of histone deacetylase 1 (HDAC1) and p130 in TGF-β1-mediated regulation of cdc25A.
- To elucidate the link between chromatin remodeling, CDK inhibition, and TGF-β1 signaling in hepatic cells.
Main Methods:
- Utilized transgenic mice with hepatic TGF-β1 overexpression.
- Performed chromatin immunoprecipitation (ChIP) assays to assess protein binding to DNA.
- Analyzed protein levels, promoter activity, and DNA synthesis in cultured cells and liver tissues.
Main Results:
- Hepatic TGF-β1 overexpression led to reduced cdc25A protein levels.
- Reduced cdc25A was associated with increased binding of HDAC1 to p130.
- HDAC1/p130 overexpression inhibited cdc25A promoter activity via an E2F site; TGF-β1 enhanced this binding.
- Hepatic proliferation decreased HDAC1 binding to p130, while cdc25A induction correlated with DNA synthesis.
Conclusions:
- TGF-β1 may inhibit cdc25A gene expression by enhancing HDAC1 binding to p130 in vivo.
- TGF-β1's regulation of HDAC1/pocket protein associations provides a link between chromatin remodeling and CDK inhibition.
- This mechanism highlights a novel pathway for TGF-β1's tumor suppressor activity involving cdc25A regulation.