Abstract
Transforming growth factor‐β (TGF‐β) inhibits epithelial cell growth, in part via transcriptional induction of the cell cycle inhibitor p21^WAF1/Cip1^ (p21). We show that bone morphogenetic protein (BMP)‐7 induces higher p21 expression than TGF‐β1 in various epithelial cells. Despite this, BMP‐7 only weakly suppresses epithelial cell proliferation, as Id2, a cell cycle‐promoting factor, becomes concomitantly induced by BMP‐7. Signaling studies with all type I receptors of the TGF‐β superfamily show that BMP receptors induce higher p21 expression than TGF‐β/activin receptors. Smad4 is essential for p21 regulation by all receptor pathways. Based on the previously known ability of c‐Myc to block p21 expression and epithelial growth arrest in response to TGF‐β1, we demonstrate that ectopic c‐Myc expression can abrogate Smad‐mediated p21 induction by all TGF‐β and BMP receptors. Furthermore, p21 induction by all receptor pathways can be blocked by the natural inhibitors of the TGF‐β superfamily. Smad7 inhibits all pathways whereas Smad6 selectively inhibits the BMP pathways. The observed pathway specificity reflects the efficiency by which BMP Smads, compared to TGF‐β Smads, transactivate the p21 promoter. In addition, BMP‐specific Smads, Smad1, Smad5, and especially Smad8, induce endogenous p21 mRNA and protein levels, while they fail to induce epithelial growth inhibition when compared to TGF‐β receptor‐phosphorylated Smads (R‐Smads), Smad2 and Smad3. Thus, p21 is a common target of all TGF‐β superfamily pathways. However, the ability of TGF‐β superfamily members to induce cell growth arrest depends on the regulation of additional gene targets. © 2005 Wiley‐Liss, Inc.