Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses.
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.
Chang
Nan-Shan
NS
Laboratory of Molecular Immunology, Guthrie Research Institute, 1 Guthrie Square, Sayre, PA 18840, USA. chang_nanshan@guthrie.org
Doherty
Joan
J
Ensign
Amy
A
Lewis
Jennifer
J
Heath
John
J
Schultz
Lori
L
Chen
Shur-Tzu
ST
Oppermann
Udo
U
D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D006333:Heart Failure; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D013312:Stress, Physiological / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases