TY - JOUR
T1 - Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses
AU - Chang, Nan Shan
AU - Doherty, Joan
AU - Ensign, Amy
AU - Lewis, Jennifer
AU - Heath, John
AU - Schultz, Lori
AU - Chen, Shur Tzu
AU - Oppermann, Udo
N1 - Funding Information:
Research was supported by the American Heart Association and the Guthrie Foundation for Education and Research (to N.-S.C.). We dedicate this work to N.-S. Chang’s second elder brother, at 61, tragically deceased in Taiwan, on December 11, 2002.
PY - 2003/10/15
Y1 - 2003/10/15
N2 - 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.
AB - 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.
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U2 - 10.1016/S0006-2952(03)00484-2
DO - 10.1016/S0006-2952(03)00484-2
M3 - Article
C2 - 14555208
AN - SCOPUS:0642283973
SN - 0006-2952
VL - 66
SP - 1347
EP - 1354
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -