Distinct roles for MAX protein isoforms in proliferation and apoptosis

MAX is a basic helix-loop-helix-leucine zipper protein that plays a central role in the transcriptional control of Myc oncoproteins. MYC-MAX heterodimers stimulate transcription, whereas MAX homodimers, or heterodimers between MAX and members of the MAD family of basic helix-loop-helix-leucine zipper proteins, repress transcription. Max exists in two major isomeric forms, MAX(L) and MAX(S), which differ from one another 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 NIH3T3 cells, MAX(L) was able to repress a c-Myc-responsive reporter gene whereas MAX(S) either stimulated the reporter gene or had little effect on its expression. In comparison to control cell lines or those stably over-expressing MAX(S), MAX(L)-over-expressing cell lines showed reduced expression of transiently expressed or endogenous c-Myc responsive genes, grew more slowly, possessed a higher growth factor requirement, and showed accelerated apoptosis following growth factor deprivation. Differential effects on growth and apoptosis represent two previously unrecognized properties of MAX proteins. These can at least partly be explained by the differences in their DNA binding abilities and their effects on target gene expression.