Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 45, Pages 30933-30940Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.051441
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Funding
- Kinderkrebshilfe Tirol
- Vorarlberg
- Provita Kinderleukamie Stiftung
- Kinderkrebshilfe Sudtirol-Regenbogen
- SVP-Frauen
- Medizinischer Forschungsfond
- Sudtiroler Krebshilfe
- Austrian Science Fund [SFB-F021]
- COMET Center ONCOTYROL
- Tyrolean Cancer Research Institute
- Tyrolean Cancer Societ
- Department of Health-Care, Autonomy of South Tyrol
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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 p(16INK4A) confers apoptosis resistance by shifting the balance of pro-and anti-apoptotic BCL2 proteins toward apoptosis protection.
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