SEARCH:   Advanced

Blood, 15 August 2008, Vol. 112, No. 4, pp. 1338-1345. Prepublished online as a Blood First Edition Paper on May 30, 2008; DOI 10.1182/blood-2007-11-124156. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-11-124156v1 112/4/1338    most recent 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 Sharma, S. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Sharma, S. Articles by Lichtenstein, A. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors Sanjai Sharma1, and Alan Lichtenstein1 1 Division of Hematology Oncology, UCLA West Los Angeles and VA Medical Center, Los Angeles, CA The mechanism by which the glucocorticoid (GC) dexamethasone induces apoptosis in multiple myeloma (MM) cells is unknown, although previous work suggests that either transactivation through the glucocorticoid response element (GRE), transrepression of NF-B, phosphorylation of RAFTK (Pyk2), or induction of Bim is important. We studied this question by ectopically expressing mutant glucocorticoid receptors (GRs) in the dexamethasone-resistant MM1R cell line, which has lost its GR. Lentiviral-mediated reexpression of wild-type GR restored GRE transactivation, NF-B transrepression, RAFTK phosphorylation, Bim induction, and dexamethasone-induced apoptosis. We then reexpressed 4 GR mutants, each possessing various molecular effects, into MM1R cells. A perfect correlation was present between induction of GRE transactivation and induction of apoptosis. In contrast, NF-B transrepression and RAFTK phosphorylation were not required for apoptosis. Although not required for dexamethasone-mediated apoptosis, NF-B inhibition achieved by gene transfer suggested that NF-B transrepression could contribute to apoptosis in dexamethasone-treated cells. Dexamethasone treatment of MM1R cells expressing a mutant incapable of inducing apoptosis successfully resulted in RAFTK (Pyk2) phosphorylation and Bim induction indicating the latter GR-mediated events were not sufficient to induce apoptosis. MM1R cells expressing mutant GRs will be helpful in defining the molecular mechanisms of dexamethasone-induced apoptosis of myeloma cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Nojima, R. Maruyama, H. Yasui, H. Suzuki, Y. Maruyama, I. Tarasawa, Y. Sasaki, H. Asaoku, H. Sakai, T. Hayashi, et al. Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma Clin. Cancer Res., July 1, 2009; 15(13): 4356 - 4364. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020