Department of Cell Biology and Cancer Center
Animals; Antigens, CD95; Apoptosis; Cell Death; Cell Division; DNA-Binding Proteins; Fas Ligand Protein; G1 Phase; Gene Expression Regulation; Histones; Interferon Regulatory Factor-2; Membrane Glycoproteins; Mice; Myeloid Progenitor Cells; *Polyploidy; *Repressor Proteins; S Phase; *Transcription Factors; Up-Regulation
Cancer Biology | Cell and Developmental Biology | Medical Cell Biology | Oncology
The IFN regulatory factor-2 (IRF-2) oncoprotein controls the cell cycle-dependent expression of histone H4 genes during S phase and may function as a component of an E2F-independent mechanism to regulate cell growth. To investigate the role of IRF-2 in control of cell proliferation, we have constructed a stable FDC-P1 cell line (F2) in which expression of IRF-2 is doxycycline (DOX)-inducible, and a control cell line (F0). Both the F2 and F0 cell lines were synchronized in the G1 phase by isoleucine deprivation, and IRF-2 was induced by DOX on release of cells from the cell cycle block. Flow cytometric analyses indicated that forced expression of IRF-2 has limited effects on cell cycle progression before the first mitosis. However, continued cell growth in the presence of elevated IRF-2 levels results in polyploidy (>4n) or genomic disintegration (<2n) and cell death. Western blot analyses revealed that the levels of the cell cycle regulatory proteins cyclin B1 and the cyclin-dependent kinase (CDK)-inhibitory protein p27 are selectively increased. These changes occur concomitant with a significant elevation in the levels of the FAS-L protein, which is the ligand of the FAS (Apo1/CD95) receptor. We also found a subtle change in the ratio of the apoptosis-promoting Bax protein and the antiapoptotic Bcl-2 protein. Hence, IRF-2 induces a cell death response involving the Fas/FasL apoptotic pathway in FDC-P1 cells. Our data suggest that the IRF-2 oncoprotein regulates a critical cell cycle checkpoint that controls progression through G2 and mitosis in FDC-P1 hematopoietic progenitor cells.
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Citation: Cancer Res. 2002 May 1;62(9):2510-5.
Xie, Ronglin; Van Wijnen, Andre J.; van der Meijden, Caroline M. J.; Stein, Janet L.; and Stein, Gary S., "Forced expression of the interferon regulatory factor 2 oncoprotein causes polyploidy and cell death in FDC-P1 myeloid hematopoietic progenitor cells" (2002). Open Access Articles. Paper 361.