ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia.
The zeta-associated protein of 70 kDa (ZAP-70) is expressed in patients with aggressive chronic lymphocytic leukemia (CLL). We found that ZAP-70+ CLL cells expressed activated heat-shock protein 90 (Hsp90) with high binding affinity for Hsp90 inhibitors, such as 17-allyl-amino-demethoxy-geldanamycin (17-AAG), whereas normal lymphocytes or ZAP-70- CLL cells expressed nonactivated Hsp90. Activated Hsp90 bound and stabilized ZAP-70, which behaved like an Hsp90 client protein only in CLL cells. Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells. Transduction of ZAP-70- CLL cells with an adenovirus encoding ZAP-70 activated Hsp90 and specifically rendered the leukemia cells sensitive to 17-AAG. These data indicate that Hsp90 is necessary for ZAP-70 expression and activity; that ZAP-70 is unique among Hsp90 clients, in that its chaperone-dependency is conditional on the cell type in which it is expressed; and also that ZAP-70 is required for cell survival and signaling in CLL. Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL.
Castro
Januario E
JE
Moores University of California San Diego (UCSD) Cancer Center, University of California, CA 92093-0960, USA. je-castro@ucsd.edu
Prada
Carlos E
CE
Loria
Olivier
O
Kamal
Adeela
A
Chen
Liguang
L
Burrows
Francis J
FJ
Kipps
Thomas J
TJ
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D016227:Benzoquinones; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007763:Lac Operon; D047029:Lactams, Macrocyclic; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011485:Protein Binding; D011809:Quinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D011947:Receptors, Antigen, B-Cell; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D017828:Rifabutin; C112765:tanespimycin; C001277:geldanamycin