SEQUENTIAL EXPRESSION OF THE MAD FAMILY OF TRANSCRIPTIONAL REPRESSORSDURING DIFFERENTIATION AND DEVELOPMENT

Members of the Myc proto-oncogene family encode transcription factors that function in multiple aspects of cell behavior, including prolifer ation, differentiation, transformation and apoptosis, Recent studies h ave shown that MYC activities are modulated by a network of nuclear bH LH-Zip proteins, The MAX protein is at the center of this network in t hat it associates with MYC as well as with the family of MAD proteins: MAD1, MXI1, MAD3 and MAD4, Whereas MYC-MAX complexes activate transcr iption, MAD-MAX complexes repress transcription through identical E-bo x binding sites, MAD proteins therefore act as antagonists of MYC, Her e we report the expression patterns of the Mad gene family in the adul t and developing mouse, High level of Mad gene expression in the adult is limited to tissues that display constant renewal of differentiated cell populations, In embryos, Marl transcripts are widely distributed with expression peaking during organogenesis at the onset of differen tiation. A detailed analysis of their pattern of expression during chr ondrocyte and neuronal differentiation in vivo, and during neuronal di fferentiation of P19 cells in vitro, shows that Mad family genes are s equentially induced, Mad3 transcripts and proteins are detected in pro liferating cells prior to differentiation. Mxi1 and Mad4 transcripts a re most abundant in cells that have further advanced along the differe ntiation pathway, whereas Mad1 is primarily expressed late in differen tiation, Taken together, our data suggest that the different members o f the MAD protein family exert their functions at distinct steps durin g the transition between proliferation and differentiation.