Linked Life Data

15516986

Source:http://linkedlifedata.com/resource/pubmed/id/15516986

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
57
pubmed:dateCreated
2004-12-13
pubmed:abstractText
Insulin receptor substrate-1 (IRS-1) mediates signaling from the insulin-like growth factor type-I receptor. We found that all-trans retinoic acid (RA) decreases IRS-1 protein levels in MCF-7, T47-D, and ZR75.1 breast cancer cells, which are growth arrested by RA, but not in the RA-resistant MDA-MB-231 and MDA-MB-468 cells. Based on prior reports of ubiquitin-mediated degradation of IRS-1, we investigated the ubiquitination of IRS-1 in RA-treated breast cancer cells. Two proteasome inhibitors, MG-132 and lactacystin, blocked the RA-mediated degradation of IRS-1, and RA increased ubiquitination of IRS-1 in the RA-sensitive breast cancer cells. In addition, we found that RA increases serine phosphorylation of IRS-1. To elucidate the signaling pathway responsible for this phosphorylation event, pharmacologic inhibitors were used. Two PKC inhibitors, but not a MAPK inhibitor, blocked the RA-induced degradation and serine phosphorylation of IRS-1. We demonstrate that RA activates PKC-delta in the sensitive, but not in the resistant cells, with a time course that is consistent with the RA-induced decrease of IRS-1. We also show that: (1) RA-activated PKC-delta phosphorylates IRS-1 in vitro, (2) PKC-delta and IRS-1 interact in RA-treated cells, and (3) mutation of three PKC-delta serine sites in IRS-1 to alanines results in no RA-induced in vitro phosphorylation of IRS-1. Together, these results indicate that RA regulates IRS-1 levels by the ubiquitin-proteasome pathway, involving a PKC-sensitive mechanism.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9269-79
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15516986-Base Sequence, pubmed-meshheading:15516986-Blotting, Northern, pubmed-meshheading:15516986-Blotting, Western, pubmed-meshheading:15516986-Cell Line, Tumor, pubmed-meshheading:15516986-DNA Primers, pubmed-meshheading:15516986-Humans, pubmed-meshheading:15516986-Hydrolysis, pubmed-meshheading:15516986-Immunoprecipitation, pubmed-meshheading:15516986-Insulin Receptor Substrate Proteins, pubmed-meshheading:15516986-Phosphoproteins, pubmed-meshheading:15516986-Phosphorylation, pubmed-meshheading:15516986-Protease Inhibitors, pubmed-meshheading:15516986-Proteasome Endopeptidase Complex, pubmed-meshheading:15516986-Protein Kinase C, pubmed-meshheading:15516986-Protein Processing, Post-Translational, pubmed-meshheading:15516986-Tretinoin, pubmed-meshheading:15516986-Ubiquitin
pubmed:year
2004
pubmed:articleTitle
Retinoic acid mediates degradation of IRS-1 by the ubiquitin-proteasome pathway, via a PKC-dependant mechanism.
pubmed:affiliation
Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital and McGill University, Departments of Oncology and Medicine, Montreal, Quebec, Canada.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.