CONTRASTING ROLES FOR MYC AND MAD PROTEINS IN CELLULAR GROWTH AND DIFFERENTIATION

The positive effects of Myc on cellular growth and gene expression are antagonized by activities of another member of the Myc superfamily, M ad. Characterization of the mouse homolog of human mad on the structur al level revealed that domains shown previously to be required in the human protein for anti-Myc repression, sequence-specific DNA-binding a ctivity, and dimerization with its partner Max are highly conserved. C onservation is also evident on the biological level in that both human and mouse mad can antagonize the ability of c-myc to cooperate with r as in the malignant transformation of cultured cells. An analysis of c -myc and mad gene expression in the developing mouse showed contrastin g patterns with respect to tissue distribution and developmental stage . Regional differences in expression were more striking on the cellula r level, particularly in the mouse and human gastrointestinal system, wherein c-Myc protein was readily detected in immature proliferating c ells at the base of the colonic crypts, while Mad protein distribution was restricted to the postmitotic differentiated cells in the apex of the crypts. An increasing gradient of Mad was also evident in the mor e differentiated subcorneal layers of the stratified squamous epitheli um of the skin. Together, these observations support the view that bot h downregulation of Myc and accumulation of Mad may be necessary for p rogression of precursor cells to a growth-arrested, terminally differe ntiated state.