Is the Loss of pRb Essential for the Mouse Skin

Abstract

The pRb pathway is inactivated in most, if not all, human and mouse tumors, including skin tumors. However, a relatively low frequency of Rb gene alterations is found. The embryonic lethality of pRb-deficient animals restricts the analysis of these mice to midgestation and precludes the analysis of the roles of pRb in mouse cancer models. To solve this problem, we used the Cre/LoxP technology to induce the tissue-specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiation but these alterations do not induce the development of spontaneous skin tumors. To gain insight in the possible roles of pRb in mouse skin carcinogenesis, we have performed chemical tumorigenesis experiments in mice bearing epidermal-specific inactivation of Rb gene. Unexpectedly, these mice develop fewer and smaller tumors than control animals, but showing increased malignant conversion to squamous cell carcinomas. Detailed biochemical analysis demonstrates that, in the absence of pRb, multiple pathways are activated leading to increased tumor apoptosis. In particular, we characterized the aberrant p53 activation mediated by E2F/p19(ARF) and other transduction pathways. This may generate a selective pressure in the tumor leading to premature p53 loss of function, which ultimately results in increased malignancy. Overall, these data highlights the role of pRb during the malignant conversion in the mouse skin carcinogenesis, and the intimate relationships between pRb and multiple tumor suppressor networks in this system.

Spontaneous Squamous Cell Carcinoma Induced by the Somatic Inactivation of Retinoblastoma and Trp53 Tumor Suppressors

“…This is in contrast with the increased apoptosis observed in the tumors generated by chemical carcinogenesis in pRb-deficient mice (19) and reinforces the previous suggestion that, on oncogenic stress, the absence of pRb can cause apoptosis in a p53-dependent manner (20). 1 The Akt and MAPK signaling pathways have been previously involved in the genesis of SCC in mouse skin (30,36,39).…”

“…On the contrary, the epidermal-specific ablation of Rb gene does not confer susceptibility to spontaneous skin tumor development (17), and on chemical carcinogenesis experiments, the absence of pRb in epidermis produced increased resistance to tumorigenesis but also higher malignant rate of conversion (19). These aspects have been previously associated to the induction of p53, which causes a selective pressure leading to the premature loss of p53 functions (19,20). In support of these findings, we have also observed that the simultaneous absence of pRb and p107 leads to spontaneous tumor formation in part through the abrogation of p53-dependent apoptotic processes (18).…”

“…1 In addition, chemical carcinogenesis protocols in these mice result in reduced number of tumors, which also show smaller size and increased malignant conversion (19). This is mediated, at least in part, by the induction of p53 and the consequent apoptosis at early stages (20). Importantly, the subsequent inactivation of p107 abolishes p53-dependent apoptotic processes, leading to spontaneous tumor formation (18).…”

Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia

“…Additionally, increased apoptosis in tumors was observed upon conditional deletion of the retinoblastoma protein. 50 Taken together, these loss-of-function experiments support a model in which the Ras/Erk MAPK pathway both stimulates as well as sustains normal epidermal proliferation and viability.…”

Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation

“…Key for embryonic and postnatal epidermal morphogenesis and homeostasis are the families of the E2F transcription factors and the retinoblastoma (pRB) protein. Alterations in the expression of either E2F or pRB proteins disrupt epidermal formation and regeneration, and contribute to tumor formation (D 'Souza et al, 2002;Chang et al, 2004;Ruiz et al, 2004Ruiz et al, , 2006. E2F factors are differentially regulated during murine keratinocyte maturation (Dagnino et al, 1997b;D'Souza et al, 2001).…”