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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Moulding, D. A. Articles by Edwards, S. W. Search for Related Content PubMed PubMed Citation Articles by Moulding, D. A. Articles by Edwards, S. W. Related Collections Hematopoiesis and Stem Cells Phagocytes Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2000, Vol. 96, No. 5, pp. 1756-1763 HEMATOPOIESIS Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells Dale A. Moulding, Richard V. Giles, David G. Spiller, Michael R. H. White, David M. Tidd, and Steven W. Edwards From the School of Biological Sciences and the Department of Haematology, University of Liverpool, Liverpool, England. Mcl-1 is a member of the Bcl-2 protein family, which has been shown to delay apoptosis in transfection and/or overexpression experiments. As yet no gene knockout mice have been engineered, and so there is little evidence to show that loss of Mcl-1 expression is sufficient to trigger apoptosis. U937 cells constitutively express the antiapoptotic protein Bcl-2; but during differentiation, in response to the phorbol ester PMA (phorbol 12 -myristate 13 -acetate), Mcl-1 is transiently induced. The purpose of this investigation was to determine the functional role played by Mcl-1 in this differentiation program. Mcl-1 expression was specifically disrupted by chimeric methylphosphonate/phosphodiester antisense oligodeoxynucleotides to just 5% of control levels. The depletion of Mcl-1 messenger RNA (mRNA) and protein was both rapid and specific, as indicated by the use of control oligodeoxynucleotides and analysis of the expression of other BCL2 family members and PMA-induced tumor necrosis factor- (TNF-). Specific depletion of Mcl-1 mRNA and protein, in the absence of changes in cellular levels of Bcl-2, results in a rapid entry into apoptosis. Levels of the proapoptotic protein Bax remained unchanged during differentiation, while Bak expression doubled within 24 hours. Apoptosis was detected within 4 hours of Mcl-1 antisense treatment by a variety of parameters including a novel live cell imaging technique allowing correlation of antisense treatment and apoptosis in individual cells. The induction of Mcl-1 is required to prevent apoptosis during differentiation of U937 cells, and the constitutive expression of Bcl-2 is unable to compensate for the loss of Mcl-1. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Dai, X. W. Meng, S.-H. Lee, P. A. Schneider, and S. H. Kaufmann Context-dependent Bcl-2/Bak Interactions Regulate Lymphoid Cell Apoptosis J. Biol. Chem., July 3, 2009; 284(27): 18311 - 18322. [Abstract] [Full Text] [PDF] M. Chopra, J. S. Reuben, and A. C. Sharma Acute Lung Injury:Apoptosis and Signaling Mechanisms Experimental Biology and Medicine, April 1, 2009; 234(4): 361 - 371. [Abstract] [Full Text] [PDF] D. A. Steimer, K. Boyd, O. Takeuchi, J. K. Fisher, G. P. Zambetti, and J. T. 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