XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313

Min Goo Lee, Jikhyon Han, Seong In Jeong, Nam Gu Her, Jin Hee Lee, Tae Kyu Ha, Min Ju Kang, Byung Kyu Ryu, Sung-Gil Chi

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growth-inhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with p53 and acts as a molecular switch in p53-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal proline-rich domain of p53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of p53. XAF1 stimulates homeodomain-interacting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of p53 by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of p53-mediated cell-cycle arrest by activating zinc finger protein 313 (ZNF313), a p21WAF1-targeting ubiquitin E3 ligase. XAF1 interacts with p53, Siah2, and ZNF313 through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to forma feedback loop with p53. Together, this study uncovers a novel role for XAF1 in p53 stress response, adding a new layer of complexity to the mechanisms by which p53 determines cell-fate decisions.

Original languageEnglish
Pages (from-to)15532-15537
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
Publication statusPublished - 2014 Oct 28

ASJC Scopus subject areas

  • General

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