Unexpected Roles for pRb in Mouse Skin Carcinogenesis

Abstract

The mouse skin carcinogenesis represents one of the best models for the understanding of malignant transformation, including the multistage nature of tumor development. The retinoblastoma gene product (pRb) plays a critical role in cell cycle regulation, differentiation, and inhibition of oncogenic transformation. In epidermis, Rb À/À deletion leads to proliferation and differentiation defects. Numerous evidences showed the involvement of the retinoblastoma pathway in this model. However, the actual role of pRb is still unknown. papillomas than the Rb +/+ counterparts. Moreover, the small size of the pRb-deficient tumors is associated with an increase in the apoptotic index. Despite this, pRb-deficient tumors display an increased conversion rate to squamous cell carcinomas. Biochemical analyses revealed that these characteristics correlate with the differential expression and activity of different pathways, including E2F/p19 arf /p53, PTEN/Akt, c-jun NH 2 -terminal kinase/p38, and nuclear factor-KB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis. (Cancer Res 2005; 65(21): 9678-86)

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

“…Our studies focused on exacerbation of existing tumorigenic phenotypes-that is, disease progression, and in this context are consistent with several animal models of Ras-mediated tumorigenesis wherein RB loss exacerbates the tumor phenotype Ho et al, 2009). Particularly, in a two-stage chemical skin carcinogenesis model, induction of DNA-damage response by direct carcinogen (DMBA) exposure or Ras activation was shown to increase the rates of acute p53-mediated apoptosis in an RB-deficient setting, ultimately limiting disease initiation (Ruiz et al, 2005;Lara et al, 2008;Santos et al, 2008). However, in this same setting, RB deficiency was shown to increase the rates of malignant conversion to carcinoma, implicating a role for RB in tumor progression.…”

Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

“…The strong activation of p53 tumor suppressor pathways may help to explain the lack of transformation of these Rb −/− MSCs. In this sense, we have previously reported the overactivation of p53 and its dependent apoptotic pathway in Rb −/− mouse models of skin carcinogenesis (50). We present data supporting the proof-of-principle that MSCs might be the target cell for transformation or the cell of origin in sarcomas.…”

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

“…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).…”