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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2003-3-21
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pubmed:abstractText |
Constitutive cell surface receptor kinase signaling and persistent phosphorylation/inactivation of the retinoblastoma (pRb) family of proteins (pRb, p107 and p130, known as pocket proteins) have been implicated in conferring uncontrolled growth to melanoma cells. However, the signals linking receptor kinase activity to neutralization of pocket proteins have not yet been fully elucidated. We therefore used specific chemical inhibitors to examine pRb regulation in melanoma cells. The most efficient agent, AG1024, known as an inhibitor of insulin-like growth factor 1 receptor and insulin receptor, arrested melanoma cell growth in vitro at nanomolar concentrations within 24 h of application. AG1024 inhibited the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and restored pRb tumor suppressive function. The latter was observed by the reduction in the phosphorylated forms of pRb, p107 and p130, and the formation of growth suppressive DNA binding complexes consisting of pRb and E2F1 or E2F3. The loss of phosphorylated forms of pRb at early time points after AG1024 application was not associated with suppression of cyclin-dependent kinases 2 and 4 activity but rather with proteasomal and nonproteasomal degradation. Thus, inhibition of melanoma cell proliferation by AG1024 is mediated by inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase 2 signaling and activation of pRb by a mechanism involving protein degradation.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/E2F Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/E2F1 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/E2F1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/E2F3 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/E2f1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoblastoma Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/tyrphostin AG 1024
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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 |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
63
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1420-9
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12649208-Animals,
pubmed-meshheading:12649208-Cell Cycle Proteins,
pubmed-meshheading:12649208-Cell Division,
pubmed-meshheading:12649208-Cyclin-Dependent Kinases,
pubmed-meshheading:12649208-DNA-Binding Proteins,
pubmed-meshheading:12649208-E2F Transcription Factors,
pubmed-meshheading:12649208-E2F1 Transcription Factor,
pubmed-meshheading:12649208-E2F3 Transcription Factor,
pubmed-meshheading:12649208-Humans,
pubmed-meshheading:12649208-MAP Kinase Signaling System,
pubmed-meshheading:12649208-Melanocytes,
pubmed-meshheading:12649208-Melanoma,
pubmed-meshheading:12649208-Mice,
pubmed-meshheading:12649208-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:12649208-Phosphorylation,
pubmed-meshheading:12649208-Retinoblastoma Protein,
pubmed-meshheading:12649208-Transcription Factors,
pubmed-meshheading:12649208-Tyrphostins,
pubmed-meshheading:12649208-Ubiquitin
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pubmed:year |
2003
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pubmed:articleTitle |
The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells.
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pubmed:affiliation |
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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