Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1.
The transcriptional activator interferon regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth. Here we report that embryonic fibroblasts (EFs) from mice with a null mutation in the IRF-1 gene (IRF-1-/- mice) can be transformed by expression of an activated c-Ha-ras oncogene. This property is not observed in EFs from wild-type or IRF-2-/- mice but is still observed in EFs from mice deficient in both genes. The transformed phenotype of ras-expressing IRF-1-/- EFs could be suppressed by the expression of the IRF-1 cDNA. Thus, IRF-1 functions as a tumor suppressor. Furthermore, expression of the c-Ha-ras oncogene causes wild-type but not IRF-1-/- EFs to undergo apoptosis when combined with a block to cell proliferation or treated by anticancer drugs or ionizing radiation. Hence, IRF-1 may be a critical determinant of oncogene-induced cell transformation or apoptosis.
Tanaka
N
N
Institute for Molecular and Cellular Biology, Osaka University, Japan.
Ishihara
M
M
Kitagawa
M
M
Harada
H
H
Kimura
T
T
Matsuyama
T
T
Lamphier
M S
MS
Aizawa
S
S
Mak
T W
TW
Taniguchi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D050856:Interferon Regulatory Factor-1; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009374:Neoplasms, Experimental / Q000209:etiology; D010750:Phosphoproteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D004247:DNA