REGULATION OF EXPRESSION AND ACTIVITY OF DISTINCT PRB, E2F, D-TYPE CYCLIN, AND CKI FAMILY MEMBERS DURING TERMINAL DIFFERENTIATION OF P19 CELLS

The cell cycle regulatory proteins, which include cyclin-dependent kin ases (cdks), cdk inhibitors (CKIs), cyclins, and the pRB, and E2F fami lies of proteins, constitute a network of interacting factors which go vern exit from or passage through the mammalian cell cycle. While the proteins within these families have similar structural characteristics , each family member exhibits distinct expression patterns during embr yogenesis and distinct biological activities, In order to begin to und erstand the tissue-specific roles of these interacting factors, we det ermined the expression pattern and activity of the pRB, E2F, cyclin, c dk, and CKI families of cell cycle regulatory proteins during retinoic acid-induced (neuronal pathway) and DMSO-induced (cardiac muscle path way) differentiation of the pluripotent murine embryonal carcinoma cel l line, P19. We demonstrate here that P19 terminal differentiation cau ses lineage-specific changes in the expression and activity of distinc t members of the E2F, pRB, cyclin, and CKI families. Furthermore, dyna mic changes in the activities of these cell cycle regulatory proteins occur through several overlapping mechanisms, culminating in repressio n of DNA-binding activity by all of the E2F family members as cells te rminally differentiate. (C) 1998 Academic Press.