Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry.
Cancer cells arise from normal cells through the acquisition of a series of mutations in oncogenes and tumour suppressor genes. Mouse models of human cancer often rely on germline alterations that activate or inactivate genes of interest. One limitation of this approach is that germline mutations might have effects other than somatic mutations, owing to developmental compensation. To model sporadic cancers associated with inactivation of the retinoblastoma (RB) tumour suppressor gene in humans, we have produced a conditional allele of the mouse Rb gene. We show here that acute loss of Rb in primary quiescent cells is sufficient for cell cycle entry and has phenotypic consequences different from germline loss of Rb function. This difference is explained in part by functional compensation by the Rb-related gene p107. We also show that acute loss of Rb in senescent cells leads to reversal of the cellular senescence programme. Thus, the use of conditional knockout strategies might refine our understanding of gene function and help to model human cancer more accurately.
Sage
Julien
J
Instituto de Biologia Molecular y Celular del Cancer, CSIC/Universidad de Salamanca, 37007-Salamanca, Spain.
Miller
Abigail L
AL
Pérez-Mancera
Pedro A
PA
Wysocki
Julianne M
JM
Jacks
Tyler
T
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D004195:Disease Models, Animal; D017353:Gene Deletion; D018390:Gene Targeting; D016161:Genes, Retinoblastoma; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology; D050720:Retinoblastoma-Like Protein p107
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; C493844:RBL1 protein, human; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107