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J. Biol. Chem., Vol. 278, Issue 17, 15272-15278, April 25, 2003
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From the Interferon regulatory factor 3 (IRF3) is
activated in response to various environmental stresses including viral
infection and DNA-damaging agents. However, the biological function of
IRF3 in cell growth is not well understood. We demonstrated that IRF3 markedly inhibited growth and colony formation of cells. IRF3 blocked
DNA synthesis and induced apoptosis. Based on this negative control of
cell growth by IRF3, we examined whether functional loss of IRF3 may
contribute to oncogenic transformation. IRF3 activity was specifically
inhibited by expression of its dominant negative mutant. This mutant
lacks a portion of the DNA binding domain like IRF3a, an alternative
splice form of IRF3 in the cells. This dominant negative inhibition
blocked expression of specific IRF3 target genes. Mutant IRF3
efficiently transformed NIH3T3 cells, as demonstrated by
anchorage-independent growth in soft agar and tumorigenicity in nude
mice. These results imply that IRF3 may function as a tumor
suppressor and suggest a possible role for the relative levels of IRF3
and its dominant negative mutant in tumorigenesis.
Oncogenic Potential of a Dominant Negative Mutant of Interferon
Regulatory Factor 3*
,,,
, and**
Department of Biological Sciences, Korea
Advanced Institute of Science and Technology, Taejon 305-701, Korea,
§ Department of Microbiology, Seoul National University,
Seoul 151-742, Korea, ¶ Samsung Biomedical Research Institute,
Sungkyunkwan University School of Medicine, Suwon 440-746, Korea, the
National Creative Research Initiative Center for Genetic
Reprogramming, Institute for Molecular Biology and Genetics, Seoul
National University, Seoul 151-742, Korea, and the
** Institute of Chemistry and Cell Biology, Department of
Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, Massachusetts 02115
*
This work was supported by the Brain Korea 21 Project of the
Korean Ministry of Education, the Molecular Medicine Research Group
Program (M1-0106-00-01117), Creative Research Initiatives, and the
Center for Biological Modulators of the 21st Century Frontier R&D
Program (CBM-01-B-5) of the Korean Ministry of Science and Technology.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biological
Sciences, Korea Advanced Inst. of Science and Technology, Taejon
305-701, Korea. Tel.: 82-42-869-2634; Fax: 82-42-869-8160; E-mail:
tkkim@ mail.kaist.ac.kr.
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