Is the Loss of pRb Essential for the Mouse Skin

• Published in: Cell cycle (Georgetown, Tex.) Vol. 5; no. 6; pp. 625 - 630
• Main Authors: Ruiz, Sergio, Santos, Mirentxu, Paramio, Jesus M.
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 16.03.2006
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cycle; Landes; Organogenesis; Proteins
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.5.6.2580

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 pRbdeficientanimals restricts the analysis of these mice to midgestation and precludes the analysis of the rolesof pRb in mouse cancer models. To solve this problem, we used the Cre/LoxP technology to induce thetissue-specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiationbut these alterations do not induce the development of spontaneous skin tumors. To gain insight in thepossible roles of pRb in mouse skin carcinogenesis, we have performed chemical tumorigenesisexperiments in mice bearing epidermal-specific inactivation of Rb gene. Unexpectedly, these mice developfewer and smaller tumors than control animals, but showing increased malignant conversion to squamouscell carcinomas. Detailed biochemical analysis demonstrates that, in the absence of pRb, multiple pathwaysare activated leading to increased tumor apoptosis. In particular, we characterized the aberrant p53activation mediated by E2F/p19ARF and other transduction pathways. This may generate a selective pressurein 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 skincarcinogenesis, and the intimate relationships between pRb and multiple tumor suppressor networks in thissystem.