Document Detail


Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells.
MedLine Citation:
PMID:  21478911     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple myeloma (MM) is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We determined the changes in gene expression induced by interleukin (IL)-6, tumor necrosis factor-α, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase serum/glucocorticoid-regulated kinase 1 (SGK1), which is a down-stream effector of PI3-kinase. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, small hairpin RNA (shRNA)-mediated knock-down of STAT3 reduced basal and induced SGK1 levels. Furthermore, downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines and reduced cell numbers. On the molecular level, this was reflected by the induction of cell cycle inhibitory genes, for example, CDKNA1/p21, whereas positively acting factors such as CDK6 and RBL2/p130 were downregulated. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth.
Authors:
U-M Fagerli; K Ullrich; T Stühmer; T Holien; K Köchert; R U Holt; O Bruland; M Chatterjee; H Nogai; G Lenz; J D Shaughnessy; S Mathas; A Sundan; R C Bargou; B Dörken; M Børset; M Janz
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-04-11
Journal Detail:
Title:  Oncogene     Volume:  30     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-14     Completed Date:  2011-09-13     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  3198-206     Citation Subset:  IM    
Affiliation:
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
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MeSH Terms
Descriptor/Qualifier:
Bone Marrow Cells / drug effects,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects,  genetics
Cytokines / metabolism,  pharmacology*
Down-Regulation / genetics
Humans
Immediate-Early Proteins / deficiency,  genetics*
Janus Kinases / metabolism
Multiple Myeloma / genetics*,  metabolism,  pathology*
Protein-Serine-Threonine Kinases / deficiency,  genetics*
RNA Interference
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects,  genetics
Transcription, Genetic / drug effects*,  genetics*
Chemical
Reg. No./Substance:
0/Cytokines; 0/Immediate-Early Proteins; 0/STAT3 Transcription Factor; EC 2.7.10.2/Janus Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/serum-glucocorticoid regulated kinase

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


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