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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.

23328673

Projects: A3.2: Cross-talk of signaling pathways and endocytic machinery in hepato..., A3.3: Hepatocyte polarity

Cell Death Dis
Cell Death Dis 4: e466
19th Jan 2013

C Meyer, Y Liu, A Kaul, I Peipe, S Dooley

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[Christoph Meyer] [Steven Dooley]

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Cell
Views: 1632
  • Created: 23rd Jan 2013 at 17:53
  • Last updated: 24th Oct 2013 at 16:15

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