P16INK4A sensitizes human leukemia cells to FAS- and glucocorticoid-induced apoptosis via induction of BBC3/Puma and repression of MCL1 and BCL2

Tyrolean Cancer Research Institute, Department of Pediatrics IV, Medical University Innsbruck, Innsbruck 6020, Austria.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 284(45):30933-40. DOI: 10.1074/jbc.M109.051441
Source: PubMed

ABSTRACT Loss of CDKN2A/p16(INK4A) in hematopoietic stem cells is associated with enhanced self-renewal capacity and might facilitate progression of damaged stem cells into pre-cancerous cells that give rise to leukemia. This is also reflected by the frequent loss of the INK4A locus in acute lymphoblastic T-cell leukemia. T-cell acute lymphoblastic leukemia cells designed to conditionally express p16(INK4A) arrest in the G(0)/G(1) phase of the cell cycle and show increased sensitivity to glucocorticoid- and tumor necrosis factor receptor superfamily 6-induced apoptosis. To investigate the underlying molecular mechanism for increased death sensitivity, we interfered with specific steps of apoptosis signaling by expression of anti-apoptotic proteins. We found that alterations in cell death susceptibility resulted from changes in the composition of pro- and anti-apoptotic BCL2 proteins, i.e. repression of MCL1, BCL2, and PMAIP1/Noxa and the induction of pro-apoptotic BBC3/Puma. Interference with Puma induction by short hairpin RNA technology or retroviral expression of MCL1 or BCL2 significantly reduced both glucocorticoid- and FAS-induced cell death in p16(INK4A)-reconstituted leukemia cells. These results suggest that Puma, in concert with MCL1 and BCL2 repression, critically mediates p16(INK4A)-induced death sensitization and that in human T-cell leukemia the deletion of p16(INK4A) confers apoptosis resistance by shifting the balance of pro- and anti-apoptotic BCL2 proteins toward apoptosis protection.

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    • "Retrovirally transduced Survivin compensates for the loss of the endogenous protein in CEM/p16-Survivin cells. Re-expression of p16INK4A accelerates death-receptor-induced (anti-FAS anibody, 0.1 mg/ml, for four hours) and glucocorticoidinduced apoptosis (10 nM dexamethasone, 24 hours) as shown in B und C (Obexer et al, 2009a). Ectopic expression of Survivin did not change the sensitivity to dexamethasone (C), but prevents increased sensitivity to Fas-induced apoptosis (B). "
    T-Cell Leukemia, Edited by Olga Babusikova, Sinisa Dovat, Kimberly J. Payne, 01/2011; InTech., ISBN: 978-953-307-400-9
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