title: E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo.
abstract: Mutational inactivation of the RB1 tumor suppressor gene initiates retinoblastoma and other human cancers. RB1 protein (pRb) restrains cell proliferation by binding E2f transcription factors and repressing the expression of cell cycle target genes. It is presumed that loss of pRb/E2f interaction accounts for tumor initiation, but this has not been directly tested. RB1 mutation is a late event in other human cancers, suggesting a role in tumor progression as well as initiation. It is currently unknown whether RB1 mutation drives tumor progression and, if so, whether loss of pRb/E2f interaction is responsible. We have characterized tumorigenesis in mice expressing a mutant pRb that is specifically deficient in binding E2f. In endocrine tissue, the mutant pRb has no detectable effect on tumorigenesis. In contrast, it significantly delays progression to invasive and lethal prostate cancer. Tumor delay is associated with induction of a senescence response. We conclude that the pRb/E2f interaction is critical for preventing tumor initiation, but that pRb can use additional context-dependent mechanisms to restrain tumor progression.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Huifang
authors.initials: H
authors.lastname: Sun
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Meenalakshmi
authors.initials: M
authors.lastname: Chinnam
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Nikitin
authors.forename: Marcia
authors.initials: M
authors.lastname: Wills
authors.forename: David W
authors.initials: DW
authors.lastname: Goodrich
mesh_terms: D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D050684:E2F Transcription Factors / Q000378:metabolism*; D016161:Genes, Retinoblastoma; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein