p107 acts as a tumor suppressor in pRb-deficient epidermis.
The specific deletion of Rb gene in epidermis leads to altered proliferation and differentiation, but not to the development of spontaneous tumors. Our previous data have demonstrated the existence of a functional compensation of Rb loss by Rbl1 (p107) in as the phenotypic differences with respect to controls are intensified. However, the possible evolution of this aggravated phenotype, in particular in relationship with tumorigenesis, has not been evaluated due to the premature death of the double deficient mice. We have now investigated whether p107 can also act as a tumor suppressor in pRb-deficient epidermis using different experimental approaches. We found spontaneous tumor development in doubly-deficient skin grafts. Moreover, Rb-deficient keratinocytes are susceptible to Ha-ras-induced transformation, and this susceptibility is enhanced by p107 loss. Further functional analyses, including microarray gene expression profiling, indicated that the loss of p107, in the absence of pRb, produces the reduction of p53-dependent pro-apoptotic signals. Overall, our data demonstrate that p107 behaves as a tumor suppressor in epidermis in the absence of pRb and suggest novel tumor-suppressive roles for p107 in the context of functional p53 and activated Ras.
Lara
M Fernanda
MF
Molecular Oncology Unit, Division of Biomedicine, CIEMAT, Madrid, Spain.
Santos
Mirentxu
M
Ruiz
Sergio
S
Segrelles
Carmen
C
Moral
Marta
M
Martínez-Cruz
Ana Belén
AB
Hernández
Pilar
P
Martínez-Palacio
Jesús
J
Lorz
Corina
C
García-Escudero
Ramón
R
Paramio
Jesús M
JM
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D016161:Genes, Retinoblastoma; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics*
C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107