Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1.
Molecular therapeutics is a recognized promising approach for melanoma, but relevant target genes remain elusive. We report that overload of the recently cloned H11/HspB8 induces apoptosis in 55% of examined melanoma cultures. Apoptosis was determined by activation of caspases-9 and -3 and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and was not seen in normal melanocytes. It was associated with H11/HspB8 complexation with transforming growth factor-beta-activated kinase (TAK) 1 and activation of TAK1 and p38 mitogen activated protein 3 kinases. TAK1 was not bound, nor activated by the H11/HspB8 mutant W51C, which has dominant antiapoptotic activity. beta-Catenin was phosphorylated by activated TAK1, inhibiting its nuclear accumulation and mictophthalmia-associated transcription factor and cyclin dependent kinase 2 expression. The dominant-negative TAK1 mutant K63W inhibited beta-catenin phosphorylation and caspase activation. The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target.
Li
B
B
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Smith
C C
CC
Laing
J M
JM
Gober
M D
MD
Liu
L
L
Aurelian
L
L
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020169:Caspases; D051357:Cyclin-Dependent Kinase 2; D004317:Doxorubicin; D006360:Heat-Shock Proteins; D020930:MAP Kinase Kinase Kinases; D051739:Microphthalmia-Associated Transcription Factor; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C413214:HSPB8 protein, human; C497234:MITF protein, human; C495894:CDK2 protein, human