PPARalpha-dependent alteration of GRP94 expression in mouse hepatocytes.
The adverse effects of the peroxisome proliferators (PPs), a class of rodent nongenotoxic hepatocarcinogens, include suppression of apoptosis, induction of hepatocyte proliferation, and liver enlargement which eventually leads to tumours. The response to PPs is mediated by the peroxisome proliferator activated receptor alpha (PPARalpha). We carried out proteomic analyses of PP-treated hepatocytes from wild-type and PPARalpha-null mice to identify the molecular pathways underlying the adverse effects of PPs. We have identified eighteen protein spots exhibiting differential expression in PP-treated wild-type mouse hepatocytes. Several proteins involved in lipid metabolism pathways, but also ATP synthase beta subunit, which are regulated by PPs were identified. In addition, both 2D silver-stained gels and Western blotting analysis indicated that the anti-apoptotic glucose-regulated protein 94 (GRP94) is consistently overexpressed upon stimulation with PPs, providing us with novel insights into the anti-apoptotic mechanism activated by PPs.
Macdonald
N
N
Cancer Biology Group, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
Barrow
K
K
Tonge
R
R
Davison
M
M
Roberts
R A
RA
Chevalier
S
S
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004261:DNA Replication; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D020025:Peroxisome Proliferators / Q000494:pharmacology; D020543:Proteome / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D020025:Peroxisome Proliferators; D020543:Proteome; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C018551:glucose-regulated proteins