Regulation of cyclin D1 expression and cell cycle progression by mitogen-activated protein kinase cascade

Mitogen-activated protein kinases (MAPKs) have been shown to play an import ant role in transducing extracellular signals into cellular responses. The classic MAPK pathway is commonly activated by growth factors and has been s hown to play a crucial role in cell proliferation. Transforming growth fact or-beta (TGF-beta)activating kinase-1 (TAK1) is a novel MAPK kinase kinase that is reported to stimulate the MKK6-p38K pathway. To elucidate the funct ional roles of the TAK1 pathway, we transfected its constitutive active for m (TAKdN) and negative form (TAKK63W) to LLC-PK1 cells. TAKdN stimulated MK K6 phosphorylation and p38K activity and inhibited the percentages of the S and G2/M phases. TAKK63W, the constitutive negative form, reduced TGF-beta -stimulated MKK6 phosphorylation and p38K activity and increased the percen tages of the S and G2/M phases. The cyclin D1 protein level is reduced by t he TAK1 pathway. We also examined the effects of the TAK1 pathway on cyclin D1 promoter-luciferase assay. The overexpression of TAKdN or p38K inhibite d cyclin D1 promoter activity. In contrast, overexpression of the active fo rm of MKK1, the classic MAPK-activator, MKK1 increased cyclin D1 promoter a ctivity and protein level, as well as the percentages of S and G2/M phases.