Interferon regulatory factor 3 activates p53-dependent cell growth inhibition.
Interferon regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection. We investigated the biological function of IRF3 overexpressed in somatic cells such as fibroblasts and astrocytes. Similar to overexpression of oncogenic H-ras in the normal human fibroblast, overexpression of IRF3 in human fibroblast BJ cells was shown to decrease cell growth and increase senescence-associated beta-galactosidase activity by activating a p53 tumor suppressor. BCNU, a DNA damage agent, further accelerated p53 function and cell death in the IRF3-overexpressed BJ cells compared to control BJ cells, without increased expression of IRF3 target genes. IRF3 failed to activate p53 function and cell growth inhibition in BJ cells downregulating p53 by RNAi-mediated p53 knockdown. Furthermore, enforced expression of IRF3 did not show any effect of cell growth inhibition in astrocytes or embryonic fibroblasts derived from the p53(-/-) mouse. When compared to control BJ cells, BJ cells which downregulated IRF3 by RNAi-mediated IRF3 knockdown showed extended in vitro life span. Taken together, the present study indicates that IRF3 should be a novel inducer of cell growth inhibition and cellular senescence through activation of p53 tumor suppressor.
Kim
Tae-Kyung
TK
The Laboratory of Cell Growth and Function Regulation, Division of Bioscience and Technology, College of Life & Environmental Sciences, Korea University, Seoul, South Korea.
Lee
Joong-Seob
JS
Jung
Ji-Eun
JE
Oh
Se-Yeong
SY
Kwak
Sungwook
S
Jin
Xun
X
Lee
Soo-Yeon
SY
Lee
Jang-Bo
JB
Chung
Yong Gu
YG
Choi
Young Ki
YK
You
Seungkwon
S
Kim
Hyunggee
H
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D050838:Interferon Regulatory Factor-3; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53