title: Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice.
abstract: Mutation of the retinoblastoma tumour-suppressor gene (RB) leads to the deregulation of many proteins and transcription factors that interact with the retinoblastoma gene product (pRB), including members of the E2F transcription factor family. As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for cell cycle progression, it is thought that pRB suppresses growth in part by repressing E2F-mediated transcription. Previously, we reported that loss of E2f1 in mice results in tissue-specific tumour induction and tissue atrophy, demonstrating that E2F-1 normally controls growth both positively and negatively in a tissue-specific fashion. To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice. We have found that loss of E2f1 reduces the frequency of pituitary and thyroid tumours, and greatly lengthens the lifespan of Rb1(+/-); E2f1(-/-) animals, demonstrating that E2F-1 is an important downstream target of pRB during tumorigenesis. Furthermore, loss of E2f1 reduces a previously reported strain-dependent difference in Rb1(+/-) lifespan, suggesting that E2f1 or an E2F-1-regulated gene acts as a genetic modifier between the 129/Sv and C57BL/6 strains.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown 02129, USA. ly63@columbia.edu
authors.forename: L
authors.initials: L
authors.lastname: Yamasaki
authors.forename: R
authors.initials: R
authors.lastname: Bronson
authors.forename: B O
authors.initials: BO
authors.lastname: Williams
authors.forename: N J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: E
authors.initials: E
authors.lastname: Harlow
authors.forename: T
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000503:physiopathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000502:physiology; D056465:Retinoblastoma-Binding Protein 1; D013045:Species Specificity; D013964:Thyroid Neoplasms / Q000235:genetics / Q000503:physiopathology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors