Source:http://linkedlifedata.com/resource/pubmed/id/11888936
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| rdf:type | |
| lifeskim:mentions |
umls-concept:C0013081,
umls-concept:C0017262,
umls-concept:C0024299,
umls-concept:C0031727,
umls-concept:C0033681,
umls-concept:C0054950,
umls-concept:C0185117,
umls-concept:C0205314,
umls-concept:C0231491,
umls-concept:C0243044,
umls-concept:C0679622,
umls-concept:C0883208,
umls-concept:C1332080,
umls-concept:C1456796,
umls-concept:C1519726,
umls-concept:C1705984,
umls-concept:C1825534,
umls-concept:C2911684
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| pubmed:issue |
5
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| pubmed:dateCreated |
2002-3-12
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| pubmed:abstractText |
Anaplastic large cell lymphomas (ALCL) are characterized by the expression of a chimeric protein, NPM-ALK, which originates from fusion of the nucleophosmin (NPM) and the membrane receptor anaplastic lymphoma kinase (ALK) genes. The NPM-ALK kinase, on dimerization, shows phosphotransferase activity and, through its interaction with various ALK-adapter proteins, induces cell transformation and increases cell proliferation in vitro. The chaperones heat shock proteins 90 (Hsp90) and 70 (Hsp70) play a critical role in the folding and maturation of several oncogenic protein kinases, and perturbation of Hsp90 structure affects the stability and degradation of Hsp90- and Hsp70-bound substrates. This process is triggered by benzoquinone ansamycin antibiotics, Hsp90-binding small molecules. We have studied the effect of 17-allylamino,17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin, on NPM-ALK steady-state level in ALCL cells. Treatment with 17-AAG decreased NPM-ALK expression and phosphorylation, thus impairing its association with phospholipase C-gamma, Src homology 2 domain-containing protein (Shc), growth factor receptor-bound protein 2 (Grb2), and insulin receptor substrate-1 (IRS-1). We also observed that NPM-ALK associates with Hsp90, and incubation with 17-AAG disrupts this complex without affecting Hsp90 expression. As shown previously for other Hsp90 client proteins, destabilization of the Hsp90/NPM-ALK complex induced by 17-AAG resulted in increased binding of the chimeric protein to Hsp70, which is known to affect protein degradation. Hsp/NPM-ALK complex formation appears to be independent of NPM sequences, because we were unable to coimmunoprecipitate NPM with either Hsp90 or Hsp70. Similar to NPM-ALK, the exogenously expressed variant fusion protein TPR-ALK showed decreased expression and phosphorylation after 17-AAG treatment, suggesting that the effect of 17-AAG on ALK chimeric proteins depends on the ALK portion and not on the partner protein moiety. Our data demonstrate that NPM-ALK cell content is determined by its interaction with Hsp90 and Hsp70, and suggest that the alteration of such associations can interfere with NPM-ALK function in ALCL cells.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/17-(allylamino)-17-demethoxygeldanam...,
http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD30,
http://linkedlifedata.com/resource/pubmed/chemical/Benzoquinones,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/HSP70 Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/HSP90 Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Lactams, Macrocyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Rifabutin,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/anaplastic lymphoma kinase,
http://linkedlifedata.com/resource/pubmed/chemical/p80(NPM-ALK) protein
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
0008-5472
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
1
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| pubmed:volume |
62
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1559-66
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| pubmed:dateRevised |
2011-11-17
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| pubmed:meshHeading |
pubmed-meshheading:11888936-Antibiotics, Antineoplastic,
pubmed-meshheading:11888936-Antigens, CD30,
pubmed-meshheading:11888936-Benzoquinones,
pubmed-meshheading:11888936-Down-Regulation,
pubmed-meshheading:11888936-Enzyme Inhibitors,
pubmed-meshheading:11888936-HSP70 Heat-Shock Proteins,
pubmed-meshheading:11888936-HSP90 Heat-Shock Proteins,
pubmed-meshheading:11888936-Humans,
pubmed-meshheading:11888936-Lactams, Macrocyclic,
pubmed-meshheading:11888936-Lymphoma, Large B-Cell, Diffuse,
pubmed-meshheading:11888936-Phosphorylation,
pubmed-meshheading:11888936-Protein-Tyrosine Kinases,
pubmed-meshheading:11888936-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:11888936-Rifabutin,
pubmed-meshheading:11888936-Tumor Cells, Cultured,
pubmed-meshheading:11888936-Tyrosine
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| pubmed:year |
2002
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| pubmed:articleTitle |
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin.
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| pubmed:affiliation |
Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, 35128 Padua, Italy. paolobonvini@hotmail.com
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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