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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2010-2-8
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pubmed:abstractText |
Expression of the VACM-1/cul5 gene in endothelial and in cancer cell lines in vitro inhibits cellular proliferation and decreases phosphorylation of MAPK. Structure-function analysis of the VACM-1 protein sequence identified consensus sites specific for phosphorylation by protein kinases A and C (PKA and PKC) and a Nedd8 protein modification site. Mutations at the PKA-specific site in VACM-1/Cul5 ((S730A)VACM-1) sequence resulted in increased cellular growth and the appearance of a Nedd8-modified VACM-1/Cul5. The aim of this study was to examine if PKA-dependent phosphorylation of VACM-1/Cul5 controls its neddylation status, phosphorylation by PKC, and ultimately growth. Our results indicate that in vitro transfection of rat adrenal medullary endothelial cells with anti-VACM-1-specific small interfering RNA oligonucleotides decreases endogenous VACM-1 protein concentration and increases cell growth. Western blot analysis of cell lysates immunoprecipitated with an antibody directed against a PKA-specific phosphorylation site and probed with anti-VACM-1-specific antibody showed that PKA-dependent phosphorylation of VACM-1 protein was decreased in cells transfected with (S730A)VACM-1 cDNA when compared with the cytomegalovirus-transfected cells. This change was associated with increased modification of VACM-1 protein by Nedd8. Induction of PKA activity with forskolin reduced modification of VACM-1 protein by Nedd8. Finally, rat adrenal medullary endothelial cells transfected with (S730A)VACM-1/cul5 cDNA and treated with phorbol 12-myristate 13-acetate (10 and 100 nm) to induce PKC activity grew significantly faster than the control cells. These results suggest that the antiproliferative effect of VACM-1/Cul5 is dependent on its posttranslational modifications and will help in the design of new anticancer therapeutics that target the Nedd8 pathway.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19917606-10092517,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19917606-10213691,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/19917606-9353339
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1083-351X
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
12
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pubmed:volume |
285
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4883-95
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pubmed:dateRevised |
2011-7-25
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pubmed:meshHeading |
pubmed-meshheading:19917606-Animals,
pubmed-meshheading:19917606-Blotting, Western,
pubmed-meshheading:19917606-Cell Line,
pubmed-meshheading:19917606-Cell Proliferation,
pubmed-meshheading:19917606-Cullin Proteins,
pubmed-meshheading:19917606-Cyclic AMP-Dependent Protein Kinases,
pubmed-meshheading:19917606-Enzyme Activation,
pubmed-meshheading:19917606-Immunoprecipitation,
pubmed-meshheading:19917606-Mutagenesis, Site-Directed,
pubmed-meshheading:19917606-Phosphorylation,
pubmed-meshheading:19917606-Protein Processing, Post-Translational,
pubmed-meshheading:19917606-RNA, Small Interfering,
pubmed-meshheading:19917606-Rats,
pubmed-meshheading:19917606-Receptors, Vasopressin,
pubmed-meshheading:19917606-Tetradecanoylphorbol Acetate,
pubmed-meshheading:19917606-Ubiquitins
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pubmed:year |
2010
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pubmed:articleTitle |
Phosphorylation of VACM-1/Cul5 by protein kinase A regulates its neddylation and antiproliferative effect.
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