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, Ho Lee Eun, Young Ki Choi, Seungkwon You, Yong Gu Chung, Jang Bo Lee, Ronald A. DePinho, Lynda Chin, Hyunggee Kim

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 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 PML-promoter-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.

Original languageEnglish
Pages (from-to)11133-11140
Number of pages8
JournalCancer Research
Volume67
Issue number23
DOIs
Publication statusPublished - 2007 Dec 1

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Interferon Regulatory Factor-3
Transcriptional Activation
Growth
Neoplasms
Virus Diseases
Innate Immunity
Promyelocytic Leukemia Protein
Cell Line
Doxycycline
Chromatin Immunoprecipitation
Acetylation
RNA Interference
Luciferases
Nude Mice
Inflammation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Direct transcriptional activation of promyelocytic leukemia protein by IFN regulatory factor 3 induces the p53-dependent growth inhibition of cancer cells. / Kim, Tae Kyung; Lee, Joong Seob; Oh, Se Yeong; Jin, Xun; Choi, Yun Jaie; Lee, Tae Hoon; Eun, Ho Lee; Choi, Young Ki; You, Seungkwon; Chung, Yong Gu; Lee, Jang Bo; DePinho, Ronald A.; Chin, Lynda; Kim, Hyunggee.

In: Cancer Research, Vol. 67, No. 23, 01.12.2007, p. 11133-11140.

Research output: Contribution to journalArticle

Kim, Tae Kyung ; Lee, Joong Seob ; Oh, Se Yeong ; Jin, Xun ; Choi, Yun Jaie ; Lee, Tae Hoon ; Eun, Ho Lee ; Choi, Young Ki ; You, Seungkwon ; Chung, Yong Gu ; Lee, Jang Bo ; DePinho, Ronald A. ; Chin, Lynda ; Kim, Hyunggee. / Direct transcriptional activation of promyelocytic leukemia protein by IFN regulatory factor 3 induces the p53-dependent growth inhibition of cancer cells. In: Cancer Research. 2007 ; Vol. 67, No. 23. pp. 11133-11140.
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