WAVE1 regulates Bcl-2 localization and phosphorylation in leukemia cells.
Bcl-2 proteins are over-expressed in many tumors and are critically important for cell survival. Their anti-apoptotic activities are determined by intracellular localization and post-translational modifications (such as phosphorylation). Here, we showed that WAVE1, a member of the Wiskott-Aldrich syndrome protein family, was over-expressed in blood cancer cell lines, and functioned as a negative regulator of apoptosis. Further enhanced expression of WAVE1 by gene transfection rendered leukemia cells more resistant to anti-cancer drug-induced apoptosis; whereas suppression of WAVE1 expression by RNA interference restored leukemia cells' sensitivity to anti-drug-induced apoptosis. WAVE1 was found to be associated with mitochondrial Bcl-2, and its depletion led to mitochondrial release of Bcl-2, and phosphorylation of ASK1/JNK and Bcl-2. Furthermore, depletion of WAVE1 expression increased anti-cancer drug-induced production of reactive oxygen species in leukemia cells. Taken together, these results suggest WAVE1 as a novel regulator of apoptosis, and potential drug target for therapeutic intervention of leukemia.
Kang
R
R
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
Tang
D
D
Yu
Y
Y
Wang
Z
Z
Hu
T
T
Wang
H
H
Cao
L
L
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000032:analysis / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D051020:bcl-X Protein; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D002118:Calcium