title: Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis.
abstract: Transforming growth factor (TGF)-β has a dual role in liver, providing cytostatic effects during liver damage and regeneration, as well as carcinogenic functions in malignant transformation and hepatocellular cancer. In cultured hepatocytes, TGF-β can trigger apoptosis and epithelial-mesenchymal transition (EMT). Caveolin-1 is associated with progression of hepatocellular cancer and has been linked to TGF-β signaling. This study aimed at elucidating whether Caveolin-1 regulates TGF-β mediated hepatocyte fate. Knockdown of Caveolin-1 strongly reduced TGF-β mediated AKT phosphorylation, thus sensitized primary murine hepatocytes for proapoptotic TGF-β signaling. Restoration of AKT activity in Caveolin-1 knockdown cells via expression of a constitutive active AKT mutant did not completely blunt the apoptotic response to TGF-β, indicating an additional mechanism how Caveolin-1 primes hepatocytes for resistance to TGF-β triggered apoptosis. On the molecular level, Caveolin-1 interfered with TGF-β initiated expression of the proapoptotic mediator BIM. Additionally, RNAi for Caveolin-1 reduced (and its overexpression increased) expression of antiapoptotic mediators BCL-2 and BCL-xl. Noteworthy, reduced Caveolin-1 protein levels had no effect on collagen 1α1, E- and N-cadherin expression upon TGF-β challenge and thus no effect on hepatocyte EMT. Hence, via affecting TGF-β mediated non-Smad AKT signaling and regulation of pro- and antiapoptotic factors, Caveolin-1 is a crucial hepatocyte fate determinant for TGF-β effects.
authors: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: C
authors: C
authors: Meyer
authors: Y
authors: Y
authors: Liu
authors: A
authors: A
authors: Kaul
authors: I
authors: I
authors: Peipe
authors: S
authors: S
authors: Dooley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015820:Cadherins / Q000378:metabolism; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015820:Cadherins; D051242:Caveolin 1; D024042:Collagen Type I; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt