Impairment of Transforming Growth Factor β Signaling in Caveolin-1-deficient Hepatocytes

Abstract

signaling decreased in the absence of Cav-1 at the time that the transcriptional corepressor SnoN accumulates. Accordingly, the expression of TGF-␤ target genes, such as plasminogen activator inhibitor-1, is decreased due to the presence of the high levels of SnoN. Moreover, hepatocyte growth factor inhibited TGF-␤ signaling in the absence of Cav-1 by increasing SnoN expression. Taken together, these data might help to unravel why Cav-1-deficient mice exhibit an accelerated liver regeneration after partial hepatectomy and add new insights on the molecular mechanisms controlling the initial commitment to hepatocyte proliferation.

Plasminogen Activator Inhibitor-1 Suppresses Profibrotic Responses in Fibroblasts from Fibrotic Lungs

“…Our findings are also consistent with the observation that TGF-␤ fails to induce PAI-1 expression and SMAD2/3 phosphorylation in fibroblasts lacking caveolin-1 expression (68). This is also true with TGF-␤-induced PAI-1 induction in hepatocytes that are caveolin-1-deficient (69). Furthermore, restoration of caveolin-1 rescues TGF-␤-mediated induction of PAI-1 expression (70) and mice lacking caveolin-1 manifest severe fibrosis after BLM injury (71).…”

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

“…TGF-␤ pathway is strongly regulated at the level of Smad activation and nuclear translocation by different means. One mechanism involves Smad sequestration in the cytosol by proteins acting as repressors such as SnoN (31,32) or AKT (33,34). However, these proteins do not seem to participate in our system, because neither SnoN knockdown nor AKT inhibition with LY294002 was able to recover response to TGF-␤ in PTP1B-deficient cells (data not shown).…”

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

“…These results are in agreement with the increased SnoN levels and improved liver regeneration in Cav-1 Ϫ/Ϫ mice, as reported recently. 51 More important, many human cancer cell lines that express high levels of SnoN are refractory to TGF-␤-induced growth arrest. 52 Altogether, these data suggest that PTP1B deficiency affects the early triggers of the regenerative response after PH and mediates gene expression related to the termination of this process.…”