The effect of FK506 on transforming growth factor beta signaling and apaptosis in chronic lymphocytic leukemia B cells (Articolo in rivista)

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  • The effect of FK506 on transforming growth factor beta signaling and apaptosis in chronic lymphocytic leukemia B cells (Articolo in rivista) (literal)
Anno
  • 2008-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.3324/haematol.12402 (literal)
Alternative label
  • Romano S; Mallardo M; Chiurazzi F; Bisogni R; D'Angelillo A; Liuzzi R; Compare G; Romano MF (2008)
    The effect of FK506 on transforming growth factor beta signaling and apaptosis in chronic lymphocytic leukemia B cells
    in Haematologica (Roma); Ferrata Storti Foundation, Pavia (Italia)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Romano S; Mallardo M; Chiurazzi F; Bisogni R; D'Angelillo A; Liuzzi R; Compare G; Romano MF (literal)
Pagina inizio
  • 1039 (literal)
Pagina fine
  • 1048 (literal)
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  • 93 (literal)
Rivista
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  • 7 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 1. Univ Naples Federico 2, Dept Biochem & Med Biotechnol, I-80131 Naples, Italy 2. CNR, Inst Biostructure Bioimaging Natl Res Council, , I-80125 Naples, Italy (literal)
Titolo
  • The effect of FK506 on transforming growth factor beta signaling and apaptosis in chronic lymphocytic leukemia B cells (literal)
Abstract
  • Background Loss of response to transforming growth factor-beta (TGF-beta) is thought to contribute to the progression of chronic lymphocytic leukemia. Recent findings of over-activation of the TGF-beta signal in FKBP12-knockout mouse prompted us to investigate whether FK506, the canonical ligand of FKBP, can activate the TGF-beta signal in chronic lymphocytic leukemia. Design and Methods We studied 62 chronic lymphocytic leukemia samples from patients with Rai/Binet stage 0 to 4 disease. The TGF-beta signal was investigated by western blotting and flow cytometry. The levels of Bcl2-family members and death-associated-protein kinase were also investigated by western blotting, whereas apoptosis was studied in flow cytometry. Down-modulation of FKBP12 was obtained by gene silencing with short interfering RNA. Results Twenty-two out of 62 chronic lymphocytic leukemia samples were sensitive to TGF-beta-induced apoptosis. All but two of the responsive samples underwent apoptosis also when cultured with FK506, but not with cyclosporine. Thirteen samples that were not sensitive to TGF-beta were sensitive to FK506. Overall, response to FK506 occurred in 33 samples. FK506 induced Smad2 phosphorylation and nuclear translocation. Accordingly, death-associated-protein kinase, a transcriptional target of Smad, was induced. At the same time, Bcl-2 and Bcl-xL levels decreased whereas the levels of Bim and Bmf increased. A loss of mitochondrial membrane potential preceded caspase activation and cell death. FK506 removed FKBP12 from its binding to the TGF-beta-receptor. FKBP12 release activated the receptor-kinase activity as suggested by the enhanced levels of phospho-Smad found in cells depleted of FKBP12. Conclusions Our study shows that most chronic lymphocytic leukemia cells escape the homeostatic control of TGF-beta and that FK506 restores the TGF-beta signal in a proportion of non-responsive samples. We demonstrated that FK506 activates TGF-beta receptor I kinase activity in chronic lymphocytic leukemia, which transduces apoptosis by a mitochondrial-dependent pathway. (literal)
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