Document Detail


Myeloid cell factor-1 is a critical survival factor for multiple myeloma.
MedLine Citation:
PMID:  11877256     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D-induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D-induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.
Authors:
Bin Zhang; Ivana Gojo; Robert G Fenton
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Blood     Volume:  99     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-03-05     Completed Date:  2002-05-23     Revised Date:  2008-07-09    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1885-93     Citation Subset:  AIM; IM    
Affiliation:
University of Maryland Greenebaum Cancer Center, Bressler Research Building, 655 W Baltimore St., Rm 7-023, Baltimore, MD 21201, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Bone Marrow / pathology
Caspases / drug effects,  metabolism
Dactinomycin / pharmacology
Enzyme Activation / drug effects
Humans
Multiple Myeloma / metabolism*,  pathology
Neoplasm Proteins / metabolism,  pharmacology,  physiology*
Protease Inhibitors / pharmacology
Proto-Oncogene Proteins c-bcl-2 / drug effects,  metabolism
Tumor Cells, Cultured
bcl-X Protein
Chemical
Reg. No./Substance:
0/BCL2L1 protein, human; 0/Neoplasm Proteins; 0/Protease Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; 50-76-0/Dactinomycin; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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