Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses

Nan Shan Chang, Joan Doherty, Amy Ensign, Jennifer Lewis, John Heath, Lori Schultz, Shur Tzu Chen, Udo Oppermann

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Human WWOX gene encodes a putative tumor suppressor WW domain-containing oxidoreductase WOX1 (also known as WWOX or FOR). A high frequency of loss of heterozygosity (LOH) of this gene has been shown in prostate, lung, breast and other cancers. In addition, numerous aberrant WWOX mRNA transcripts have been found in cancer cells. WOX1 is a proapoptotic protein. In response to stress or apoptotic stimuli, WOX1 became phosphorylated at Tyr33, which enabled its complex formation with activated p53 and JNK1. The p53/WOX1 complex translocated to the mitochondria and further to the nuclei to mediate apoptosis. WOX1 mutants, which were inactivated for nuclear translocation or Tyr33 phosphorylation, failed to induce apoptosis, indicating that activation of WOX1 via Tyr33 phosphorylation, followed by nuclear translocation, is essential for inducing cell death. WOX1 induced apoptosis synergistically with p53. In contrast, transiently activated JNK1 induced anti-apoptotic response, and this protective activity inhibited WOX1-induced apoptosis. Taken together, WOX1 is involved in stress and apoptotic responses, and is likely to regulate the activation of both p53 and JNK1.

Original languageEnglish
Pages (from-to)1347-1354
Number of pages8
JournalBiochemical Pharmacology
Volume66
Issue number8
DOIs
Publication statusPublished - 2003 Oct 15

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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