Differential regulation of p34^cdc2 and p33^cdk2 by transforming growth factor‐β₁ in murine mammary epithelial cells

Cyclin‐dependent kinases (cdks) are a family of proteins whose function plays a critical role in cell cycle traverse. Transforming growth factor‐β₁ (TGF‐β₁) is a potent growth inhibitor of epithelial cells. Since cdks have been suggested as possible biochemical markers for TGF‐β growth inhibition, we investigated the effect of TGF‐β₁ on cdc2 and cdk2 in a normal mouse mammary epithelial cell line (MME) and a TGF‐β‐resistant MME cell line (BG18.2). TGF‐β₁ decreases newly synthesized cdc2 protein levels within 6 h after addition. Coincident with this decrease in newly synthesized cdc2 protein was a marked reduction in its ability to phosphorylate histone H1. This decrease in kinase activity is not due to a change in steady‐state levels of cdc2 protein, since mRNA and total protein levels of cdc2 are not reduced until 12 h after TGF‐β₁ addition. This suggests that the kinase activity of cdc2 is dependent on newly synthesized cdc2 protien. Moreover, the protein synthesis of another cyclin‐dependent kinase, cdk2, is not effected by TGF‐β₁ addition, but its kinase activity is substantially reduced. Thus, it appears that TGF‐β decreases the kinase activity of both cdc2 and cdk2 by distinct mechanisms.