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Oncogenic potential of a dominant negative mutant of interferon regulatory factor 3
Tae Young Kim1, Kyoung-Hu Lee, Seungwoo Chang
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.
Abstract:
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.
Insights
Interferon regulatory factor 3 (IRF3) inhibits cell growth and induces apoptosis. Loss of IRF3 function promotes oncogenic transformation, suggesting IRF3 acts as a tumor suppressor.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Interferon regulatory factor 3 (IRF3) is activated by environmental stresses like viral infections.
- The role of IRF3 in regulating cell growth and its potential involvement in cancer are not fully understood.
Purpose of the Study:
- To investigate the biological function of IRF3 in cell growth.
- To determine if functional loss of IRF3 contributes to oncogenic transformation.
Main Methods:
- Assessed the impact of IRF3 on cell growth, DNA synthesis, and apoptosis.
- Utilized a dominant-negative IRF3 mutant to inhibit IRF3 activity.
- Evaluated NIH3T3 cell transformation through anchorage-independent growth and tumorigenicity assays.
Main Results:
- IRF3 significantly inhibited cell growth and colony formation.
- IRF3 blocked DNA synthesis and induced apoptosis.
- Inhibition of IRF3 activity by a dominant-negative mutant led to NIH3T3 cell transformation, including anchorage-independent growth and tumor formation in mice.
Conclusions:
- IRF3 functions as a suppressor of cell growth and may act as a tumor suppressor.
- The balance between IRF3 and its dominant-negative mutant may play a role in tumorigenesis.