Transforming growth factor-β1 inhibits cyclin D1 expression in intestinal epithelial cells

Transforming growth factor-β1 (TGP-β1) inhibits most epithelial cell types by blocking cell cycle progression during the G₁ phase. D cyclins are normally expressed during G₁ and are regulators of G₁ progression. One of the crucial functions of D cyclins is their ability to bind to a cyclin-dependent kinase (Cdk4). In mink lung epithelial cells, TGF-β1 inhibits Cdk4 expression. We have measured cell cycle progression and D cyclins and Cdk4 expression in non-transformed rat intestinal epithelial cell lines (IEC-6 and RIE-1) after TGF-β1 treatment. In exponentially growing cultures, TGF-β1 blocked DNA synthesis and suppressed cyclin D1 mRNA and protein expression, whereas the levels of cyclins D2, D3 and Cdk4 remained relatively unchanged. TGF-β1 was also added to G₀-synchronized IEC-6 cells after serum stimulation. TGF-β1 prevention of G₁ progression was associated with an inhibition of cyclin D1 protein expression. Cyclin D3 levels were not affected by TGF-β1 during G₁ traverse. Our results suggest that cyclin D/ Cdk4 is a crucial target of TGF-β1 and that regulation of this kinase is mediated through cyclin D1 in intestinal epithelial cells.