DIFFERENTIAL-EFFECTS BY MAD AND MAX ON TRANSFORMATION BY CELLULAR ANDVIRAL ONCOPROTEINS

c-Myc is an essential component of the regulatory mechanisms controlli ng cell growth. Max is the obligatory partner of c-Myc for all its bio logical functions analysed to date. Recently two Max interacting prote ins, Mad and Mxi1, have been identified. It has been suggested that th ese two proteins modulate c-Myc function, in the simplest model by com peting with c-Myc for the interaction with Max. We have analysed diffe rent aspects of Mad function in comparison to Max, Native Mad/Max hete rodimers bound specifically to a c-Myc/Max consensus DNA binding site. Furthermore Mad inhibited efficiently c-Myc, mutant p53, adenovirus E la, or human papilloma virus type 16 transformation of rat embryo cell s in cooperation with activated Ha-Ras, Myc transformed clones showed an increased cell cycle time and a reduced immortalization frequency a fter cotransfection with either mad or max. In contrast to Mad, Max di d not inhibit E1a/Ha-Ras cotransformation but repressed c-Myc/Ha-Ras t ransformation efficiently. Mad Delta N, an N-terminal deletion mutant of Mad, was as efficient in repressing c-Myc/Ha-Ras cotransformation a s full length Mad but showed little inhibitory activity when assayed o n E1a/Ha-Ras. Unlike wt Mad, Mad Delta N had little effect on cell gro wth. Our data suggest that Mad affects cell growth at least in part by a c-Myc independent mechanism.