Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis.
The retinoblastoma gene product, pRb, plays a crucial role in cell cycle regulation, differentiation and inhibition of oncogenic transformation. pRb and its closely related family members p107 and p130 perform exclusive and overlapping functions during mouse development. The embryonic lethality of Rb-null animals restricts the phenotypic analysis of these mice to mid-gestation embryogenesis. We employed the Cre/loxP system to study the function of Rb in adult mouse stratified epithelium. Rb(F19/F19);K14cre mice displayed hyperplasia and hyperkeratosis in the epidermis with increased proliferation and aberrant expression of differentiation markers. In vitro, pRb is essential for the maintainance of the postmitotic state of terminally differentiated keratinocytes, preventing cell cycle re-entry. However, p107 compensates for the effects of Rb loss as the phenotypic abnormalities of Rb(F19/F19);K14cre keratinocytes in vivo and in vitro become more severe with the concurrent loss of p107 alleles. p107 alone appears to be dispensable for all these phenotypic changes, as the presence of a single Rb allele in a p107-null background rescues all these alterations. Luciferase reporter experiments indicate that these phenotypic alterations might be mediated by increased E2F activity. Our findings support a model in which pRb in conjunction with p107 plays a central role in regulating epidermal homeostasis.
Ruiz
Sergio
S
Department of Cell and Molecular Biology and Gene Therapy, CIEMAT, Madrid E28040, Spain.
Santos
Mirentxu
M
Segrelles
Carmen
C
Leis
Hugo
H
Jorcano
José Luis
JL
Berns
Anton
A
Paramio
Jesús M
JM
Vooijs
Marc
M
D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107; D012867:Skin / Q000473:pathology; D013234:Stem Cells / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; C489485:Rbl1 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D014157:Transcription Factors