Oncogenic potential of a dominant negative mutant of interferon regulatory factor 3.
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.
Kim
Tae Young
TY
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.
Lee
Kyoung-Hu
KH
Chang
Seungwoo
S
Chung
Cheolho
C
Lee
Han-Woong
HW
Yim
Jeongbin
J
Kim
Tae Kook
TK
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites / Q000235:genetics; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins