| Autor: |
Roberts, RA, James, NH, Woodyatt, NJ, Macdonald, N, Tugwood, JD |
| Zdroj: |
Carcinogenesis; Jan1998, Vol. 19 Issue 1, p43-48, 6p |
| Abstrakt: |
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-β1 (TGFβ1). PPs transcriptionally activate the peroxisome proliferator activated receptor-alpha (PPARα), a member of the nuclear hormone receptor superfamily. Here, we investigate whether activation of PPARα mediates the suppression of rat hepatocyte apoptosis induced by PPs. We isolated a naturally occurring variant form of PPARα (hPPARα-6/29) from human liver by PCR cloning. Electrophoretic mobility shift assays (EMSA) demonstrated that hPPARα-6/29 shared the ability of mPPARα to heterodimerise with the retinoid X receptor (RXR) and bind to DNA. When hPPARα-6/29 was transfected into Hepa1c1c7 cells together with a reporter plasmid containing a PPAR response element (PPRE), hPPARα-6/29, unlike mPPARα, could not be activated by PPs. Furthermore, hPPARα-6/29 could act as a dominant negative regulator of PPAR-mediated gene transcription since increasing concentrations of hPPARα-6/29 abrogated the activation of co-transfected mPPARα. When introduced into primary rat liver cell cultures by transient transfection, hPPARα-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 PPARα 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 PPARα provides a survival signal for hepatocytes, preventing their death in response to apoptotic stimuli. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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