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Suppression of hepatocyte apoptosis by non-genotoxic carcinogens
Başlık:
Suppression of hepatocyte apoptosis by non-genotoxic carcinogens
Yazar:
Gill, Jason Harry, author.
ISBN:
9780438083097
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (230 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
The peroxisome proliferators (PPs) are a structurally diverse group of rodent non-genotoxic hepatocarcinogen. In order to assess the risk these chemicals pose to humans, the mechanism(s) responsible for their hepatocarcinogenicity must be established. One hypothesis is that PPs suppress hepatocyte apoptosis and increase the rate of cell division, thereby allowing the survival and proliferation of potentially tumourigenic cells. A role for the suppression of apoptosis was supported by both in vitro and in vivo studies which demonstrated that PPs could suppress spontaneous hepatocyte apoptosis and that induced by transforming growth factor-beta1 (TGF beta1). Furthermore, this suppression is dependent upon activation of the transcription factor, peroxisome proliferator activated receptor alpha (PPARalpha). In this thesis, the molecular mechanisms responsible for the suppression of hepatocyte apoptosis by the PP, nafenopin were investigated in vitro using both rat and mouse hepatocytes. As predicted, nafenopin suppressed apoptosis in the majority quiescent population of hepatocytes and elevated CDK4, a cell cycle progression factor, supporting the theory that PPs permit the survival and promotion of potentially tumourigenic cells. Treatment of hepatocyte monolayers with TGF beta1, DNA damaging agents, or with an agonistic anti-Fas antibody induced high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all these stimuli. This implies that nafenopin suppresses apoptosis by impinging on a core regulator of apoptosis. Many potential sites exist within the apoptotic pathway for regulation by nafenopin. No change in expression of the tumour suppressor, p53 was observed after DNA damage, and this together with other published data on p53 in the liver suggest that a role for p53 in the action of nafenopin is unlikely. Furthermore, the suppression of apoptosis by nafenopin does not appear to require Fas or involve a modulation of Fas-ligand or c-FLIP, an inhibitor of Fas-induced apoptosis. Another potential target for nafenopin is the Bcl-2 family of proteins, known to be central regulators of apoptosis in many cell systems. An involvement for the anti-apoptotic member, Bcl-2, or the pro-apoptotic member, Bax-xL in the regulation of hepatocyte apoptosis or in cell survival mediated by nafenopin was not supported. In contrast, the anti- apoptotic member Bcl-XL was 1.2-1.5 fold higher in a mitochondrial enriched fraction isolated from nafenopin treated hepatocytes compared to non-treated controls, a change that was not detectable in whole cell lysates. Similarly, levels of cytochrome c, which is known to activate the caspase cascade upon release from mitochondria into the cytosol, was also marginally higher in mitochondria isolated from nafenopin treated hepatocytes. Therefore, since cytochrome c release is regulatable by Bcl-XL, this may imply that nafenopin upregulates mitochondrial Bcl-XL levels thereby preventing cytochrome c release, activation of the caspase cascade, and suppressing apoptosis. In support of this hypothesis, nafenopin also prevented activation of the executionary caspases. While these investigations did not identify conclusively the molecular mechanism(s) by which PPs suppress apoptosis, the results presented in this thesis suggest that nafenopin may modulate apoptotic events in mitochondria.
Notlar:
School code: 1543
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(686866.1) | 686866-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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