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IGF-1 suppresses Bi...
IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms
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De Bruyne, Elke (author)
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Bos, Tomas J. (author)
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Schuit, Frans (author)
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Van Valckenborgh, Els (author)
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Menu, Eline (author)
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Thorrez, Lieven (author)
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Atadja, Peter (author)
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- Jernberg-Wiklund, Helena (author)
- Uppsala universitet,Institutionen för genetik och patologi
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Vanderkerken, Karin (author)
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(creator_code:org_t)
- American Society of Hematology, 2010
- 2010
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:12, s. 2430-2440
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Insulin-like growth factor-1 (IGF-1) is an important growth and survival factor in multiple myeloma (MM). Here, we demonstrate that IGF-1 induces significant down-regulation of the proapoptotic BH3-only protein Bim in MM cells. Reduced Bim levels by RNA interference (RNAi) protected cells from drug-induced cell death. The IGF-1-mediated down-regulation of Bim was the result of (1) reduced transcription by activation of the Akt pathway and inactivation of the transcription factor FoxO3a, (2) increased proteasome-mediated degradation of the Bim extra-long protein by activation of the mitogen-activated protein kinase pathway, and (3) epigenetic regulation of both the Bim and the FoxO3a promoter. Treatment of cells with the histone deacetylase inhibitor LBH589 resulted in a clear up-regulation in the expression of Bim. Furthermore, the methylation inhibitor 5-aza-2'deoxycytidine (decitabine) significantly increased the effects of LBH589. On IGF-1 treatment, the Bim promoter region was found to be unmethylated, whereas chromatin immunoprecipitation analysis of the IGF-1-treated cells showed both a reduced histone H3 tail Lys9 (H3K9) acetylation and an increased H3K9 dimethylation, which contributed actively to its silencing. These data identify a new mechanism in the IGF-1-dependent survival of MM cells and emphasize the need for IGF-1-targeted drug therapy.
Keyword
- MEDICINE
- MEDICIN
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- ref (subject category)
- art (subject category)
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