Susceptibility of pRb-deficient epidermis to chemical skin carcinogenesis is dependent on the p107 allele dosage.
Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.
Santos
Mirentxu
M
Molecular Oncology Unit, Division of Biomedicine, CIEMAT, Madrid, Spain.
Ruiz
Sergio
S
Lara
M Fernanda
MF
Segrelles
Carmen
C
Moral
Marta
M
Martínez-Cruz
Ana Belén
AB
Ballestín
Claudio
C
Lorz
Corina
C
García-Escudero
Ramón
R
Paramio
Jesús M
JM
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D002273:Carcinogens; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107