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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 publication

DOI

10.1016/s0006-2952(03)00484-2

Type

Journal article

Journal

Biochemical pharmacology

Publication Date

10/2003

Volume

66

Pages

1347 - 1354

Addresses

Laboratory of Molecular Immunology, Guthrie Research Institute, 1 Guthrie Square, Sayre, PA 18840, USA. chang_nanshan@guthrie.org

Keywords

Cell Nucleus, Mitochondria, Humans, Oxidoreductases, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 8, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Apoptosis, Protein Structure, Tertiary, Biological Transport, Phosphorylation, Tumor Suppressor Protein p53, Heart Failure, Stress, Physiological