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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2003-6-9
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pubmed:abstractText |
Sustained extracellular signal-regulated kinase 1/2 (ERK1/2) activation does not always correlate with its upstream Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) signal cascade in cancer cells, and the mechanism remains elusive. Here we report a novel mechanism by which sustained ERK1/2 activation is established. We demonstrate that Pb(II), a carcinogenic metal, persistently induces ERK1/2 activity in CL3 human lung cancer cells and that Ras-Raf-MKK1/2 signaling cannot fully account for such activation. It is intriguing that Pb(II) treatment reduces mitogen-activated protein kinase phosphatase 1 (MKP-1) protein levels in time- and dose-dependent manners, which correlates with sustained ERK1/2 activation, and that Pb(II) also induces mRNA and de novo protein synthesis of MKP-1. In Pb(II)-treated cells, MKP-1 is polyubiquitinated, and proteasome inhibitors markedly alleviate the ubiquitination and degradation of MKP-1. Inhibiting the Pb(II)-induced ERK1/2 activation by PD98059 greatly suppresses MKP-1 ubiquitination and degradation. It is remarkable that constitutive activation of MKK1/2 triggers endogenous MKP-1 ubiquitination and degradation in various mammalian cell lines. Furthermore, expression of functional MKP-1 decreases ERK1/2 activation and the c-Fos protein level and enhances cytotoxicity under Pb(II) exposure. Taken together, these results demonstrate that activated ERK1/2 can trigger MKP-1 degradation via the ubiquitin-proteasome pathway, thus facilitating long-term activation of ERK1/2 against cytotoxicity.
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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/DUSP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Dual Specificity Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
21534-41
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12676937-Animals,
pubmed-meshheading:12676937-Blotting, Northern,
pubmed-meshheading:12676937-Blotting, Western,
pubmed-meshheading:12676937-CHO Cells,
pubmed-meshheading:12676937-Cricetinae,
pubmed-meshheading:12676937-Dose-Response Relationship, Drug,
pubmed-meshheading:12676937-Dual Specificity Phosphatase 1,
pubmed-meshheading:12676937-Enzyme Activation,
pubmed-meshheading:12676937-Enzyme Inhibitors,
pubmed-meshheading:12676937-Flavonoids,
pubmed-meshheading:12676937-Humans,
pubmed-meshheading:12676937-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:12676937-Mitogen-Activated Protein Kinase 3,
pubmed-meshheading:12676937-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12676937-Models, Biological,
pubmed-meshheading:12676937-Precipitin Tests,
pubmed-meshheading:12676937-Protein Binding,
pubmed-meshheading:12676937-Protein Biosynthesis,
pubmed-meshheading:12676937-Protein Phosphatase 1,
pubmed-meshheading:12676937-Protein Tyrosine Phosphatases,
pubmed-meshheading:12676937-RNA, Messenger,
pubmed-meshheading:12676937-Signal Transduction,
pubmed-meshheading:12676937-Time Factors,
pubmed-meshheading:12676937-Transcription, Genetic,
pubmed-meshheading:12676937-Transfection,
pubmed-meshheading:12676937-Tumor Cells, Cultured,
pubmed-meshheading:12676937-Ubiquitin
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pubmed:year |
2003
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pubmed:articleTitle |
ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway.
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pubmed:affiliation |
Molecular Carcinogenesis Laboratory, Institute of Biotechnology, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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