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Biol Open. 2012 Mar 15;1(3):247-60. doi: 10.1242/bio.2012463. Epub 2012 Feb 3.

Nuclear Smad7 Overexpressed in Mesenchymal Cells Acts as a Transcriptional Corepressor by Interacting with HDAC-1 and E2F to Regulate Cell Cycle.

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1
Present address: Department of Immunology and Inflammatory Diseases, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

Abstract

Smad family proteins are essential intracellular mediators that regulate transforming growth factor-β (TGF-β) ligand signaling. In response to diverse stimuli, Smad7 is rapidly expressed and acts as a cytoplasmic inhibitor that selectively interferes with signals elicited from TGF-β family receptors. In addition, earlier works have indicated that retrovirally transduced Smad7 induces long-lasting cell proliferation arrest in a variety of mesenchymal cells through down-regulation of G1 cyclins. However, the molecular mechanisms underlying the cytostatic effects of Smad7 remain unknown. We show here that Smad7 can form a complex with endogenous histone deacetylase proteins HDAC-1 and HDAC-3 in NIH 3T3 mouse fibroblast cells. By contrast, forced expression of a dominant-negative variant of HDAC-1 efficiently protected cells against Smad7 proliferation inhibition, suggesting that Smad7 depends on the deacetylase activity of its associated HDAC-1 to arrest the cell cycle. Furthermore, Smad7 caused HDAC-1 bind to E2F-1 to form a ternary complex on chromosomal DNA containing an E2F-binding motif and leading to repression in the activity of the E2F target genes. Smad7 mutations that prevented its binding to either HDAC-1 or E2F-1 resulted in a significant decrease in Smad7-mediated inhibition of cell proliferation. The present results strongly suggest that nuclear Smad7 is a transcriptional corepressor for E2F, providing a molecular basis for the Smad7-induced arrest of the cell cycle.

KEYWORDS:

Cell cycle; E2F; Histone deacetylase; Smad; Transcriptional corepressor

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