FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2549930601> ?p ?o ?g. }

• W2549930601 abstract "Abstract Abstract 2452 Deletion of chromosome 5q in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients results in loss of miR-146a, which is a negative regulator of the innate immune pathway by targeting TNF receptor associated factor-6 (TRAF6). Therefore, MDS and AML patients with reduced miR-146a expression concomitantly exhibit elevated TRAF6 protein. TRAF6 is an E3 ubiquitin ligase that catalyzes K63-linked polyubiquitin chains on substrates that lead to pathway activation, one of which includes NF-kB. Mice lacking miR-146a, or with overexpression of TRAF6, develop AML- and MDS-like features. Bortezomib (Velcade©), which shows promise alone or in combination with chemotherapy in certain groups of MDS and AML patients, is a selective and reversible inhibitor of the 26S proteasome. Studies on the mechanism of action of Bortezomib have shown that pro-apoptotic proteins are stabilized following proteasome inhibition and contribute to the anti-cancer effect. In this report, paradoxically, we find that Bortezomib induces rapid and complete degradation of TRAF6 protein, but not mRNA, in MDS/AML cell lines and human CD34+ cells. A similar finding was observed when AML cells were treated with MG132, another proteasome inhibitor, indicating that degradation of TRAF6 is secondary to proteasomal inhibition. Interestingly, the reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, as indicated by conversion of LC3B-I to LC3B-II and degradation of SQSTM1/p62, and subsequently with apoptosis in MDS/AML cells. Addition of an autophagy inhibitor (3-methyladenine [3-MA]) to Bortezomib-treated AML cells maintained TRAF6 protein expression and enhanced cell viability. Similarly, TRAF6 degradation was blocked by 3-MA when cells were treated with Rapamycin, an mTOR inhibitor and inducer of autophagy. These findings suggest that a mechanism of Bortezomib-induced cell death in myeloid malignancies involves elimination of TRAF6 protein by autophagosomes. Forced expression of TRAF6 in two AML cell lines partially blocked the cytotoxic effect of Bortezomib, suggesting that TRAF6 is an important target of Bortezomib. To determine whether loss of TRAF6 is sufficient to impede growth of MDS and AML, we used a genetic approach to inhibit TRAF6 in MDS/AML cell lines and bone marrow cells from MDS patients with deletion of chromosome 5q. RNAi-mediated depletion of TRAF6 in MDS and AML samples resulted in impaired malignant hematopoietic stem/progenitor function and rapid apoptosis. To uncover the molecular consequences following loss of TRAF6, we applied gene expression profiling and identified genes relevant to the survival of MDS and AML cells. In summary, these findings implicate TRAF6 in Bortezomib-induced cell death and in the maintenance of myeloid malignancies, and reveal a novel mechanism of TRAF6 regulation through autophagic degradation. Disclosures: Oliva: Celgene: Consultancy." @default.
• W2549930601 created "2016-11-30" @default.
• W2549930601 creator A5000522683 @default.
• W2549930601 creator A5009827973 @default.
• W2549930601 creator A5033305440 @default.
• W2549930601 creator A5037735415 @default.
• W2549930601 creator A5041711274 @default.
• W2549930601 creator A5056930112 @default.
• W2549930601 creator A5068661721 @default.
• W2549930601 creator A5070924011 @default.
• W2549930601 date "2011-11-18" @default.
• W2549930601 modified "2023-09-27" @default.
• W2549930601 title "Degradation of TRAF6 by Bortezomib-Induced Autophagy Contributes to Cell Death in Acute Myeloid Leukemia and Myelodysplastic Syndrome" @default.
• W2549930601 doi "https://doi.org/10.1182/blood.v118.21.2452.2452" @default.
• W2549930601 hasPublicationYear "2011" @default.
• W2549930601 type Work @default.
• W2549930601 sameAs 2549930601 @default.
• W2549930601 citedByCount "0" @default.
• W2549930601 crossrefType "journal-article" @default.
• W2549930601 hasAuthorship W2549930601A5000522683 @default.
• W2549930601 hasAuthorship W2549930601A5009827973 @default.
• W2549930601 hasAuthorship W2549930601A5033305440 @default.
• W2549930601 hasAuthorship W2549930601A5037735415 @default.
• W2549930601 hasAuthorship W2549930601A5041711274 @default.
• W2549930601 hasAuthorship W2549930601A5056930112 @default.
• W2549930601 hasAuthorship W2549930601A5068661721 @default.
• W2549930601 hasAuthorship W2549930601A5070924011 @default.
• W2549930601 hasConcept C104317684 @default.
• W2549930601 hasConcept C134459356 @default.
• W2549930601 hasConcept C185592680 @default.
• W2549930601 hasConcept C190283241 @default.
• W2549930601 hasConcept C203014093 @default.
• W2549930601 hasConcept C203522944 @default.
• W2549930601 hasConcept C25602115 @default.
• W2549930601 hasConcept C27740335 @default.
• W2549930601 hasConcept C2776364478 @default.
• W2549930601 hasConcept C2777478702 @default.
• W2549930601 hasConcept C2778367456 @default.
• W2549930601 hasConcept C2778461978 @default.
• W2549930601 hasConcept C2778506107 @default.
• W2549930601 hasConcept C2778729363 @default.
• W2549930601 hasConcept C2779282312 @default.
• W2549930601 hasConcept C2992195973 @default.
• W2549930601 hasConcept C502942594 @default.
• W2549930601 hasConcept C55493867 @default.
• W2549930601 hasConcept C86803240 @default.
• W2549930601 hasConcept C95444343 @default.
• W2549930601 hasConceptScore W2549930601C104317684 @default.
• W2549930601 hasConceptScore W2549930601C134459356 @default.
• W2549930601 hasConceptScore W2549930601C185592680 @default.
• W2549930601 hasConceptScore W2549930601C190283241 @default.
• W2549930601 hasConceptScore W2549930601C203014093 @default.
• W2549930601 hasConceptScore W2549930601C203522944 @default.
• W2549930601 hasConceptScore W2549930601C25602115 @default.
• W2549930601 hasConceptScore W2549930601C27740335 @default.
• W2549930601 hasConceptScore W2549930601C2776364478 @default.
• W2549930601 hasConceptScore W2549930601C2777478702 @default.
• W2549930601 hasConceptScore W2549930601C2778367456 @default.
• W2549930601 hasConceptScore W2549930601C2778461978 @default.
• W2549930601 hasConceptScore W2549930601C2778506107 @default.
• W2549930601 hasConceptScore W2549930601C2778729363 @default.
• W2549930601 hasConceptScore W2549930601C2779282312 @default.
• W2549930601 hasConceptScore W2549930601C2992195973 @default.
• W2549930601 hasConceptScore W2549930601C502942594 @default.
• W2549930601 hasConceptScore W2549930601C55493867 @default.
• W2549930601 hasConceptScore W2549930601C86803240 @default.
• W2549930601 hasConceptScore W2549930601C95444343 @default.
• W2549930601 hasLocation W25499306011 @default.
• W2549930601 hasOpenAccess W2549930601 @default.
• W2549930601 hasPrimaryLocation W25499306011 @default.
• W2549930601 hasRelatedWork W1480336412 @default.
• W2549930601 hasRelatedWork W1965532751 @default.
• W2549930601 hasRelatedWork W1994441995 @default.
• W2549930601 hasRelatedWork W2024203756 @default.
• W2549930601 hasRelatedWork W2032061143 @default.
• W2549930601 hasRelatedWork W2051899176 @default.
• W2549930601 hasRelatedWork W2083193063 @default.
• W2549930601 hasRelatedWork W2086048608 @default.
• W2549930601 hasRelatedWork W2087488820 @default.
• W2549930601 hasRelatedWork W2139123529 @default.
• W2549930601 hasRelatedWork W2156019676 @default.
• W2549930601 hasRelatedWork W2431850463 @default.
• W2549930601 hasRelatedWork W2466297657 @default.
• W2549930601 hasRelatedWork W2529224904 @default.
• W2549930601 hasRelatedWork W2530276238 @default.
• W2549930601 hasRelatedWork W2589096622 @default.
• W2549930601 hasRelatedWork W2735492323 @default.
• W2549930601 hasRelatedWork W2999815456 @default.
• W2549930601 hasRelatedWork W3092915417 @default.
• W2549930601 hasRelatedWork W3106688515 @default.
• W2549930601 isParatext "false" @default.
• W2549930601 isRetracted "false" @default.
• W2549930601 magId "2549930601" @default.
• W2549930601 workType "article" @default.