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Abstract
E2F activity is critical for the control of the G1 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.
ACKNOWLEDGMENTS
S.J.F. is supported by a Howard Hughes Medical Institute (HHMI) Postdoctoral Fellowship. S.H.O. is an investigator of HHMI. M.G. is supported by NIH grants R01 CA43855 and P30-HD18655 from the Mental Retardation Center. R.D.C. is supported, in part, by grant 5JB-0014 from the State of California Breast Cancer Research Program. J.D. is supported by grants from the NIH (RO1 CA77314-01) and the American Cancer Society (RSG LIB-101051) and by a Scholar Award from the Leukemia and Lymphoma Society.
We thank the following individuals for critical review of the manuscript: P. Marrack, D. Bentley, T. Van Dyke, J. Hagman, A. Gutierrez-Hartmann, J. Nevins, D. DcRyckere, and N. Jones. We also thank K. Helm, P. Schor, and M. Ashton of the Cancer Center Flow Cytometry Core (supported by grant 2 P30 CA 46934-09), P. Skavlen and CLAC for excellent veterinary care, J. Torvik and D. Wegman for cytokine measurements, and J. Cambier and B. Benschop for reagents and advice concerning B-cell differentiation. We thank Ana Zubiaga for sharing unpublished data. We also thank Leslie Bloomquist for histological processing, supported by Diabetes Endocrinology Research Center grant P30 DR 57516.