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BIN1 tumor suppressor regulates Fas/Fas ligand-mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma.
- Source :
-
Leukemia (08876924) . Jun2015, Vol. 29 Issue 6, p1402-1413. 12p. 2 Diagrams, 4 Graphs. - Publication Year :
- 2015
-
Abstract
- The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4+CD7− Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 29
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 103024706
- Full Text :
- https://doi.org/10.1038/leu.2015.9