title: A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice.
abstract: The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report, we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1(ΔG)) are defective for pRB-dependent repression of E2F target genes. Except for an accelerated entry into S phase in response to serum stimulation, cell cycle regulation in Rb1(ΔG/ΔG) mouse embryonic fibroblasts (MEFs) strongly resembles that of the wild type. In a serum deprivation-induced cell cycle exit, Rb1(ΔG/ΔG) MEFs display a magnitude of E2F target gene derepression similar to that of Rb1(-/-) cells, even though Rb1(ΔG/ΔG) cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1(ΔG/ΔG) MEFs is responsive to p16 expression and gamma irradiation, indicating that alternate mechanisms can be activated in G1 to arrest proliferation. Some Rb1(ΔG/ΔG) mice die neonatally with a muscle degeneration phenotype, while the others live a normal life span with no evidence of spontaneous tumor formation. Most tissues appear histologically normal while being accompanied by derepression of pRB-regulated E2F targets. This suggests that non-E2F-, pRB-dependent pathways may have a more relevant role in proliferative control than previously identified.
authors.affiliation: London Regional Cancer Program, Western University, London, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thwaites
authors.forename: Srikanth
authors.initials: S
authors.lastname: Talluri
authors.forename: James I
authors.initials: JI
authors.lastname: MacDonald
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Passos
authors.forename: Jean-Leon
authors.initials: JL
authors.lastname: Chong
authors.forename: Paul
authors.initials: P
authors.lastname: Cantalupo
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stafford
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Sáenz-Robles
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Francis
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000483:Alleles; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050684:E2F Transcription Factors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*; D016196:S Phase / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein