title: E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis.
abstract: E2F activity is critical for the control of the G(1) to S phase transition. We show that the combined loss of E2F1 and E2F2 results in profound effects on hematopoietic cell proliferation and differentiation, as well as increased tumorigenesis and decreased lymphocyte tolerance. The loss of E2F1 and E2F2 impedes B-cell differentiation, and hematopoietic progenitor cells in the bone marrow of mice lacking E2F1 and E2F2 exhibit increased cell cycling. Importantly, we show that E2F1 and E2F2 double-knockout T cells exhibit more rapid entry into S phase following antigenic stimulation. Furthermore, T cells lacking E2F1 and E2F2 proliferate much more extensively in response to subthreshold antigenic stimulation. Consistent with these observations, E2F1/E2F2 mutant mice are highly predisposed to the development of tumors, and some mice exhibit signs of autoimmunity.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Zhu
authors.forename: S J
authors.initials: SJ
authors.lastname: Field
authors.forename: L
authors.initials: L
authors.lastname: Gore
authors.forename: M
authors.initials: M
authors.lastname: Thompson
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: R D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: M
authors.initials: M
authors.lastname: Greenberg
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.forename: J
authors.initials: J
authors.lastname: DeGregori
mesh_terms: D000367:Age Factors; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D008198:Lymph Nodes / Q000166:cytology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*
chemical_list: D000941:Antigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; C493754:E2f1 protein, mouse; D014157:Transcription Factors; D012260:Ribonucleases; D001973:Bromodeoxyuridine