Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Tae-Kyung Kim, Joong-Seob Lee, Se-Yeong Oh, Xun Jin, Yun-Jaie Choi, Tae-Hoon Lee, Eun ho Lee, Young-Ki Choi, Seungkwon You, Yong Gu Chung, Jang-Bo Lee, Ronald A. DePinho (+2 others)
2007 Cancer Research  
IFN 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, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting
more » ... ng IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PMLpromoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007; 67(23):11133-40]
doi:10.1158/0008-5472.can-07-1342 pmid:18056437 fatcat:hm5izgadrbcxrmubapahebinim