The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta

Transforming growth factor-beta (TGF-beta)can induce the cyclin-dependent k inase inhibitors p21 and p15 in a variety of cell types. We have shown prev iously that Smad3 is required for the growth inhibitory activity of TGF-bet a, whereas overexpression of Smads is not sufficient to activate the expres sion of p21 in HaCaT cells. These data suggest that an additional signaling pathway may be involved in stimulating p21 in HaCaT cells. Given the recen t finding that the mitogen-activated protein kinase (MAPK) pathway can caus e p21 induction and arrest cells, we examined the involvement of this pathw ay for p21 and p15 induction by TGF-beta, We found that TGF-beta can regula te the MAPK pathway, leading to the increased transactivation ability of tr anscription factor Elk, Constitutively active components in the MAPK pathwa y activate pal expression, and inhibitors or dominant negative constructs f or the MAPK pathway significantly decrease p21 induction by TGF-beta, Both constitutively active MEK and inhibitors for MEK have no effect on Smad act ivity, including DNA binding, localization, and interaction with coactivato r p800/CBP, These findings suggest that the MAPK pathway may be an independ ent pathway that is involved in p21 and p15 induction by TGF-beta.