REGULATION OF MYC AND MAD DURING EPIDERMAL DIFFERENTIATION AND HPV-ASSOCIATED TUMORIGENESIS

c-Myc and Mad each form heterodimers with Max that bind the same E-box related DNA sequences, Whereas Myc:Max complexes activate transcripti on and promote cell proliferation and transformation, Mad:Max complexe s repress transcription and block c-Myc-mediated cell transformation. Here we examine these antagonistic transcription factors during epithe lial differentiation and neoplastic progression, During differentiatio n of primary human keratinocytes, Mad is rapidly induced and c-Myc is downregulated, resulting in a switch from c-Myc:Max to Mad:Max heterod imers, In normal epidermis and colonic mucosa c-myc expression is prol iferating cell layers, while mad restricted to differentiating cell la yers, Using HPV18 transformed keratinocytes that vary in their ability to differentiate in organotypic cultures, we find that Mad induction occurs only in those cells that retain a differentiation response, In the epidermis of transgenic mice in which expression of the HPV16 E6 a nd E7 oncogenes are targeted to basal keratinocytes, neoplastic progre ssion occurs and is marked by an expansion of c-myc expressing basal-l ike cells. Expression of mad is found only in growth-arrested differen tiating cells on the outer edges of preneoplastic lesions, The squamou s cell carcinomas that arise evidence a variable number of sites withi n the tumor masses where mad expression and morphological differentiat ion coincide; increasing malignancy correlates with loss of both mad a nd capability to differentiate, These results indicate that c-Myc and Mad expression are tightly coupled to the transition from proliferatio n to differentiation of epithelial cells and that restriction of Mad e xpression may be associated with loss of normal differentiation capabi lity and with tumorigenesis.