p16INK4A Sensitizes Human Leukemia Cells to FAS- and Glucocorticoid-induced Apoptosis via Induction of BBC3/Puma and Repression of MCL1 and BCL2 |
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Authors: | Petra Obexer Judith Hagenbuchner Martina Rupp Christina Salvador Markus Holzner Martin Deutsch Verena Porto Reinhard Kofler Thomas Unterkircher Michael J. Ausserlechner |
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Affiliation: | From the ‡Tyrolean Cancer Research Institute and ;the Departments of §Pediatrics IV and ;¶Pediatrics II and ;‖Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innsbruck 6020, Austria |
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Abstract: | Loss of CDKN2A/p16INK4A 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 p16INK4A arrest in the G0/G1 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 p16INK4A-reconstituted leukemia cells. These results suggest that Puma, in concert with MCL1 and BCL2 repression, critically mediates p16INK4A-induced death sensitization and that in human T-cell leukemia the deletion of p16INK4A confers apoptosis resistance by shifting the balance of pro- and anti-apoptotic BCL2 proteins toward apoptosis protection. |
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