An evolutionary view of the Myc network in growth control and differentiation

Abstract

Myc family oncoproteins are believed to function as regulators of target genes involved in growth, differentiation, and programmed cell death. Activities of the transactivation-competent Myc/Max heterodimer are in turn modulated by transactivation-inert complexes (including Max/Max, Mxi1/Max, and Mad/Max) that can bind to the Myc/Max consensus core in a repressive fashion. The rationale for isolating homologs of this interacting network of proteins from lower vertebrate organisms was twofold--(i) the maintenance of key structural and functional properties throughout vertebrate evolution would suggest conservation of proposed models on Myc activity and regulation, and (ii) these models could then be verified in the more experimentally-manipulatable systems that these organisms provide. Several diverse approaches resulted in the isolation of newly-identified genes encoding Xenopus L-Myc1 and L-Myc2, zebra fish c-, N-, L-Myc and Max, and zebra fish and mouse Mxi1.;Structural conservation of Myc and Max motifs believed to be important for dimerization, DNA binding, and nuclear localization was paralleled by functional conservation as assessed by the rat embryo fibroblast cooperation (REF) assay. In particular, Myc homologs (in most cases) from Xenopus and zebra fish were also capable of transforming primary mammalian cells to malignancy, and zebra fish max could suppress mouse c-Myc transforming activity to the same degree as its mammalian counterpart. Finally, steady state mRNA expression analyses during embryogenesis of these two lower vertebrates showed that each myc family gene exhibited a distinct expression profile, suggesting separable, but perhaps also compensatory, developmental roles. With respect to Mxi1, its putative role as a negative regulator of Myc activity by its ability to compete for both Max and common target sites was supported by the reciprocal mRNA expression patterns of mxi1 and myc during progression to the terminally differentiated state and the tumor suppressor activity of mxi1 in the REF assay.;In summary, this doctoral dissertation provides insight into the roles of members of the Myc family and their associated proteins in vertebrate growth and development and fortifies proposed models on the regulation of Myc responsive targets from an evolutionary standpoint.