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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 20, 2007 Accepted March 17, 2008 Dexamethasone induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors Sanjai Sharma* and Alan Lichtenstein Hematology Oncology, UCLA West LA VAMC, Los Angeles, CA, United States * Corresponding author; email: sasharma{at}mednet.ucla.edu. The mechanism by which the glucocorticoid (GC) dexamethasone (dex) 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 dex-resistant MM1R cell line which has lost its GR. Lentiviral mediated re-expression of wild type GR restored GRE transactivation, NF-B transrepression, RAFTK phosphorylation, Bim induction and dex-induced apoptosis. We then re-expressed four GR mutants, each possessing varying 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 was not required for apoptosis. Although not required for dex-mediated apoptosis, NF-B inhibition achieved by gene transfer suggested that NF-B transrepression could contribute to apoptosis in dex-treated cells. Dex 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 dex-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