Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
1998-2-27
|
| pubmed:abstractText |
Peroxisome proliferators (PPs) are a class of nongenotoxic rodent hepatocarcinogens. We have demonstrated previously that PPs suppress both spontaneous rat hepatocyte apoptosis and that induced by exogenous stimuli such as transforming growth factor-beta1 (TGFbeta1). PPs transcriptionally activate the peroxisome proliferator activated receptor-alpha (PPAR alpha), a member of the nuclear hormone receptor superfamily. Here, we investigate whether activation of PPAR alpha mediates the suppression of rat hepatocyte apoptosis induced by PPs. We isolated a naturally occurring variant form of PPAR alpha (hPPAR alpha-6/29) from human liver by PCR cloning. Electrophoretic mobility shift assays (EMSA) demonstrated that hPPAR alpha-6/29 shared the ability of mPPAR alpha to heterodimerise with the retinoid X receptor (RXR) and bind to DNA. When hPPAR alpha-6/29 was transfected into Hepa1c1c7 cells together with a reporter plasmid containing a PPAR response element (PPRE), hPPAR alpha-6/29, unlike mPPAR alpha, could not be activated by PPs. Furthermore, hPPAR alpha-6/29 could act as a dominant negative regulator of PPAR-mediated gene transcription since increasing concentrations of hPPAR alpha-6/29 abrogated the activation of co-transfected mPPAR alpha. When introduced into primary rat liver cell cultures by transient transfection, hPPAR alpha-6/29 prevented the suppression of hepatocyte apoptosis by the PP nafenopin, but not that seen in response to phenobarbitone (PB), a nongenotoxic carcinogen whose action does not involve PPAR alpha. The suppression of hepatocyte apoptosis was abrogated completely even though only 30% of hepatocytes were transfected, suggesting the involvement of a soluble factor. These data indicate that activation of rat liver PPAR alpha provides a survival signal for hepatocytes, preventing their death in response to apoptotic stimuli.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA Primers,
http://linkedlifedata.com/resource/pubmed/chemical/Lymphotoxin-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jan
|
| pubmed:issn |
0143-3334
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
19
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
43-8
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9472691-Amino Acid Sequence,
pubmed-meshheading:9472691-Animals,
pubmed-meshheading:9472691-Apoptosis,
pubmed-meshheading:9472691-Base Sequence,
pubmed-meshheading:9472691-Carcinoma, Hepatocellular,
pubmed-meshheading:9472691-Cells, Cultured,
pubmed-meshheading:9472691-DNA Primers,
pubmed-meshheading:9472691-Genes, Reporter,
pubmed-meshheading:9472691-Humans,
pubmed-meshheading:9472691-Liver,
pubmed-meshheading:9472691-Liver Neoplasms,
pubmed-meshheading:9472691-Lymphotoxin-alpha,
pubmed-meshheading:9472691-Male,
pubmed-meshheading:9472691-Mice,
pubmed-meshheading:9472691-Nuclear Proteins,
pubmed-meshheading:9472691-Polymerase Chain Reaction,
pubmed-meshheading:9472691-Rats,
pubmed-meshheading:9472691-Rats, Wistar,
pubmed-meshheading:9472691-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:9472691-Recombinant Proteins,
pubmed-meshheading:9472691-Sequence Alignment,
pubmed-meshheading:9472691-Transcription Factors,
pubmed-meshheading:9472691-Transfection,
pubmed-meshheading:9472691-Tumor Cells, Cultured
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR alpha).
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| pubmed:affiliation |
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK. ruth.roberts@CTL.ZENECA.com
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| pubmed:publicationType |
Journal Article
|