Cell cycle regulation of histone H4 gene transcription requires the oncogenic factor IRF-2.
Histone genes display a peak in transcription in early S phase and are ideal models for cell cycle-regulated gene expression. We have previously shown that the transcription factor interferon regulatory factor 2 (IRF-2) can activate histone H4 gene expression. In this report we establish that a mouse histone H4 gene and its human homolog lose stringent cell cycle control in synchronized embryonic fibroblasts in which IRF-2 has been ablated. We also show that there are reduced mRNA levels of this endogenous mouse histone H4 gene in the IRF-2(-/-) cells. Strikingly, the overall mRNA level and cell cycle regulation of histone H4 transcription are restored when IRF-2 is reintroduced to these cells. IRF-2 is a negative regulator of the interferon response and has oncogenic potential, but little is known of the mechanism of these activities. Our results suggest that IRF-2 is an active player in E2F-independent cell cycle-regulated gene expression at the G1/S phase transition. IRF-2 was previously considered a passive antagonist to the tumor suppressor IRF-1 but can now join other oncogenic factors such as c-Myb and E2F1 that are predicted to mediate their transforming capabilities by actively regulating genes necessary for cell cycle progression.
Vaughan
P S
PS
Department of Cell Biology and Cancer Center, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA.
van der Meijden
C M
CM
Aziz
F
F
Harada
H
H
Taniguchi
T
T
van Wijnen
A J
AJ
Stein
J L
JL
Stein
G S
GS
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000235:genetics*; D006801:Humans; D050836:Interferon Regulatory Factor-2; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D006657:Histones; C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D015500:Chloramphenicol O-Acetyltransferase