Unexpected roles for pRb in mouse skin carcinogenesis.
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-/- 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. To study the possible involvement of pRb in keratinocyte malignant transformation, we have carried out two-stage chemical skin carcinogenesis on Rb(F19/F19) (thereafter Rb+/+) and Rb(F19/F19);K14Cre (thereafter Rb-/-) animals. Unexpectedly, we found that Rb-/- mice developed fewer and smaller 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/p19arf/p53, PTEN/Akt, c-jun NH2-terminal kinase/p38, and nuclear factor-kappaB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis.
Ruiz
Sergio
S
Program on Cell and Molecular Biology, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas and Department of Pathology, Hospital 12 de Octubre, Madrid, Spain.
Santos
Mirentxu
M
Lara
M Fernanda
MF
Segrelles
Carmen
C
Ballestín
Claudio
C
Paramio
Jesús M
JM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D050684:E2F Transcription Factors / Q000378:metabolism; D051379:Mice; D010212:Papilloma / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002273:Carcinogens; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene