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

被引：68

作者：

Fagerli, U-M ^{[2
,3
]}

Ullrich, K. ^{[1
,4
]}

Stuehmer, T. ^{[5
,6
]}

Holien, T. ^{[2
]}

Koechert, K. ^{[1
,4
]}

Holt, R. U. ^{[2
,7
]}

Bruland, O. ^{[8
]}

Chatterjee, M. ^{[5
,6
]}

Nogai, H. ^{[1
]}

Lenz, G. ^{[1
]}

Shaughnessy, J. D., Jr. ^{[9
]}

Mathas, S. ^{[1
,4
]}

Sundan, A. ^{[2
]}

Bargou, R. C. ^{[5
,6
]}

Doerken, B. ^{[1
,4
]}

Borset, M. ^{[2
,10
]}

Janz, M. ^{[1
,4
]}

机构：

[1] Campus Virchow Klinikum, Univ Med Sch Berlin, Charite, Dept Hematol Oncol & Tumorimmunol, D-13092 Berlin, Germany

[2] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7034 Trondheim, Norway

[3] St Olavs Univ Hosp, Dept Oncol, Trondheim, Norway

[4] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany

[5] Univ Hosp Wurzburg, Dept Internal Med 2, Wurzburg, Germany

[6] Univ Hosp Wurzburg, Comprehens Canc Ctr Mainfranken, Div Hematol, Wurzburg, Germany

[7] Sor Trondelag Univ Coll, Fac Technol, Dept Biomed Sci, Trondheim, Norway

[8] Haukeland Univ Hosp Bergen, Ctr Med Genet & Mol Med, Bergen, Norway

[9] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA

[10] St Olavs Univ Hosp, Dept Immunol & Transfus Med, Trondheim, Norway

来源：

ONCOGENE | 2011年 / 30卷 / 28期

关键词：

multiple myeloma; cytokines; SGK1; STAT3; PROTEIN-KINASE; BONE-MARROW; EPITHELIAL-CELLS; SURVIVAL; SERUM; PATHWAY; ACTIVATION; EXPRESSION; APOPTOSIS; DOWNSTREAM;

D O I：

10.1038/onc.2011.79

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-alpha, 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. Oncogene (2011) 30, 3198-3206; doi:10.1038/onc.2011.79; published online 11 April 2011

引用

页码：3198 / 3206

页数：9

共 22 条

[1] Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation [J].