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J. Biol. Chem., Vol. 276, Issue 27, 24453-24456, July 6, 2001
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,,, and
From Smac, a second mitochondria-derived activator of
caspases, promotes caspase activation in the cytochrome c
(cyto-c)/Apaf-1/caspase-9 pathway. Here, we show that
treatment of multiple myeloma (MM) cells with dexamethasone (Dex)
triggers the release of Smac from mitochondria to cytosol and activates
caspase-9 without concurrent release of cyto-c and Apaf-1
oligomerization. Smac binds to XIAP (an inhibitor of apoptosis protein)
and thereby, at least in part, eliminates its inhibitory effect on
caspase-9. Interleukin-6, a growth factor for MM, blocks
Dex-induced apoptosis and prevents release of Smac. Taken together,
these findings demonstrate that Smac plays a functional role in
mediating Dex-induced caspase-9 activation and apoptosis in MM cells.
The Jerome Lipper® Multiple Myeloma Center,
Department of Adult Oncology, Dana Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts 02115, the
§ Northwestern University Medical School, Robert H. Lurie
Cancer Center, Chicago, Illinois 60611, and ¶ The Burnham
Institute, La Jolla, California 92037
To whom correspondence should be addressed: Adult Oncology,
Dana Farber Cancer Institute, Mayer 557, 44 Binney St., Boston, MA 02115. Tel.: 617-632-2144; Fax: 617-632-2569; E-mail:
kenneth_anderson@dfci.harvard.edu.
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C. Yu, G. Krystal, P. Dent, and S. Grant Flavopiridol Potentiates STI571-induced Mitochondrial Damage and Apoptosis in BCR-ABL-positive Human Leukemia Cells Clin. Cancer Res., September 1, 2002; 8(9): 2976 - 2984. [Abstract] [Full Text] [PDF]
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D. Chauhan, L. Catley, T. Hideshima, G. Li, R. Leblanc, D. Gupta, M. Sattler, P. Richardson, R. L. Schlossman, K. Podar, et al. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells Blood, August 28, 2002; 100(6): 2187 - 2194. [Abstract] [Full Text] [PDF]
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M. Akiyama, T. Hideshima, T. Hayashi, Y.-T. Tai, C. S. Mitsiades, N. Mitsiades, D. Chauhan, P. Richardson, N. C. Munshi, and K. C. Anderson Cytokines Modulate Telomerase Activity in a Human Multiple Myeloma Cell Line Cancer Res., July 1, 2002; 62(13): 3876 - 3882. [Abstract] [Full Text] [PDF]
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M. Rehm, H. Dussmann, R. U. Janicke, J. M. Tavare, D. Kogel, and J. H. M. Prehn Single-cell Fluorescence Resonance Energy Transfer Analysis Demonstrates That Caspase Activation during Apoptosis Is a Rapid Process. ROLE OF CASPASE-3 J. Biol. Chem., June 28, 2002; 277(27): 24506 - 24514. [Abstract] [Full Text] [PDF]
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R. V. Rao, S. Castro-Obregon, H. Frankowski, M. Schuler, V. Stoka, G. del Rio, D. E. Bredesen, and H. M. Ellerby Coupling Endoplasmic Reticulum Stress to the Cell Death Program. AN Apaf-1-INDEPENDENT INTRINSIC PATHWAY J. Biol. Chem., June 7, 2002; 277(24): 21836 - 21842. [Abstract] [Full Text] [PDF]
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S. Greenstein, K. Ghias, N. L. Krett, and S. T. Rosen Mechanisms of Glucocorticoid-mediated Apoptosis in Hematological Malignancies Clin. Cancer Res., June 1, 2002; 8(6): 1681 - 1694. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Blood, May 29, 2002; 99(12): 4525 - 4530. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, P. Richardson, C. Mitsiades, N. Mitsiades, T. Hayashi, N. Munshi, L. Dang, A. Castro, V. Palombella, et al. NF-kappa B as a Therapeutic Target in Multiple Myeloma J. Biol. Chem., May 3, 2002; 277(19): 16639 - 16647. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, D. Gupta, P. Richardson, N. Munshi, and K. C. Anderson The Biological Sequelae of Stromal Cell-derived Factor-1{alpha} in Multiple Myeloma Mol. Cancer Ther., May 1, 2002; 1(7): 539 - 544. [Abstract] [Full Text] [PDF]
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W. S. Dalton, P. L. Bergsagel, W. M. Kuehl, K. C. Anderson, and J. L. Harousseau Multiple Myeloma Hematology, January 1, 2001; 2001(1): 157 - 177. [Abstract] [Full Text] [PDF]
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B. B. Wolf, M. Schuler, W. Li, B. Eggers-Sedlet, W. Lee, P. Tailor, P. Fitzgerald, G. B. Mills, and D. R. Green Defective Cytochrome c-dependent Caspase Activation in Ovarian Cancer Cell Lines due to Diminished or Absent Apoptotic Protease Activating Factor-1 Activity J. Biol. Chem., August 31, 2001; 276(36): 34244 - 34251. [Abstract] [Full Text] [PDF]
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L. M. Martins, I. Iaccarino, T. Tenev, S. Gschmeissner, N. F. Totty, N. R. Lemoine, J. Savopoulos, C. W. Gray, C. L. Creasy, C. Dingwall, et al. The Serine Protease Omi/HtrA2 Regulates Apoptosis by Binding XIAP through a Reaper-like Motif J. Biol. Chem., January 4, 2002; 277(1): 439 - 444. [Abstract] [Full Text] [PDF]
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