AbstractIn contrast with the low frequency of alterations found in the Rb gene, the pRb pathway is inactivated in the vast majority of human tumors. A similar situation takes place in mouse models of cancer, including two‐stage skin tumorigenesis. This might be explained if the Rb functions are carried out, in its absence, by other proteins that are also controlled by the same upstream regulators and display similar effectors. The other Rb family members, p107 and or p130, are plausible candidates. The embryonic lethality of pRb‐deficient animals, which precludes the analysis of the roles of Rb gene in mouse models, has been avoided using tissue‐specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiation. However, these deficient mice do not develop spontaneous tumors, and chemical carcinogenesis experiments revealed that the absence of pRb renders fewer and smaller tumors than control animals, but showing increased malignant conversion to squamous cell carcinomas (SCC). Detailed biochemical analyses have indicated that, in the absence of pRb, multiple pathways, including the aberrant p53 activation mediated by E2F/p19ARF, are activated leading to increased tumor apoptosis. As Rb loss in epidermis is functionally compensated by Rbl1 (p107), this might also suggest that p107 could behave as a tumor suppressor. We summarize here our findings in support of this hypothesis. The pRb−;p107−/− epidermis form spontaneous tumors, and the reduction of p107 levels restores the susceptibility of pRb‐mice to chemical skin carcinogenesis experiments. Moreover, Rb‐deficient keratinocytes are highly susceptible to Ha‐ras‐induced transformation, and this susceptibility is enhanced by p107 loss. Further functional studies have indicated that the loss of p107 in the absence of pRb produces the reduction of p53‐dependent proapoptotic signals through the modulation of p63 and p73 isoforms. In addition, expression profiling analysis has revealed multiple oncogenic alterations that can contribute to tumor susceptibility in epidermis in the absence of pRb and p107. © 2007 Wiley‐Liss, Inc.