DISTINCT ROLES FOR MAX PROTEIN ISOFORMS IN PROLIFERATION AND APOPTOSIS

MAX is a basic helix-loop-helix-leucine zipper protein that plays a ce ntral role in the transcriptional control of Myc oncoproteins. MYC-MAX heterodimers stimulate transcription, whereas MAX homodimers, or hete rodimers between MAX and members of the MAD family of basic helix-loop -helix-leuciue zipper proteins, repress transcription, Max exists in t wo major isomeric forms, MAX(L) and MAX(S), which differ from one anot her only by a 9-amino acid insertion/deletion. We show here that MAX(L ) is much more effective at homodimeric DNA binding than MAX(S). In NI H3T3 cells, MAX(L) was able to repress a c-Myc-responsive reporter gen e whereas MAX(S) either stimulated the reporter gene or had little eff ect on its expression. Hn comparison to control cell lines or those st ably over-expressing MAX(S), MAX(L)-over-expressing cell lines showed reduced expression of transiently expressed or endogenous c-Myc respon sive genes, grew more slowly, possessed a higher growth factor require ment, and showed accelerated apoptosis following growth factor depriva tion, Differential effects on growth and apoptosis represent two previ ously unrecognized properties of MAX proteins. These can at least part ly be explained by the differences in their DNA binding abilities and their effects on target gents expression.