REGULATION OF G(1) PROGRESSION BY E2A AND ID HELIX-LOOP-HELIX PROTEINS

In NIH3T3 fibroblasts, the ubiquitous helix-loop-helix (HLH) protein E 2A (E12/E47) and the myogenic HLH proteins MyoD, MRF4 and myogenin are growth-inhibitory, while two ubiquitous Id proteins lacking the basic region are not. The dimerization domain mediates inhibition. However, in addition to the HLH region, E2A contains two inhibitory regions ov erlapping with the main transcriptional activation domains. The growth -suppressive activity of the intact E47 as well as MyoD was counteract ed bp the Id proteins. When E47 lacking the HLH domain was overexpress ed, Id could no longer reverse growth inhibition. By increasing the am ount of E47 with an inducible system or neutralizing the endogenous Id with microinjected anti-Id antibodies, withdrawal from the cell cycle occurred within hours before the G(1)-S transition point. The combine d results suggest that the Id proteins are required for G(1) progressi on. The antagonism between the E2A and Id proteins further suggests th at both are involved in regulatory events prior to or near the restric tion point in the G(1) phase of the cell cycle.