TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

Kim, Hyun-Kyoung; Bhattarai, Kashi Raj; Junjappa, Raghu Patil; Ahn, Jin Hee; Pagire, Suvarna H.; Yoo, Hyun Ju; Han, Jaeseok; Lee, Duckgue; Kim, Kyung-Woon; Kim, Hyung‐Ryong; Chae, Han‐Jung

doi:10.1038/s41467-020-17802-4

Cited by 40 publications

(34 citation statements)

References 66 publications

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“…AKT was first discovered as an oncogene in leukemia ( 3 ), it regulates the proliferation, metabolism, angiogenesis, migration, and invasion of cancer cells ( 4 , 5 ). Aberrant activation of AKT was found in many adult tumors, such as multiple myeloma ( 6 , 7 ), renal cancer ( 8 ), lung cancer ( 9 ), prostate cancer ( 10 ), and liver cancer ( 11 ). Hyperactivation of AKT has been explored as a new poor prognostic factor for NB patients and is significantly correlated with MYCN amplification and advanced stage ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells

et al. 2021

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BackgroundChemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases; however, its roles in NB have not been established. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK-2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells.MethodsThe expressions of ATXN3 and BCL-2 family members were detected by Western blot. Cell survival was evaluated by CCK8, cell confluence was measured by IncuCyte, and apoptosis was detected by flow cytometry. AS and BE2 were treated with AKT inhibitors or chemotherapeutics, respectively.ResultsDownregulation of ATXN3 did not block, but significantly increased the perifosine/MK-2206-induced cell death. Among the BCL-2 family members, the expression of pro-apoptotic protein BIM and anti-proapoptotic protein Bcl-xl expression increased significantly when ATXN3 was down-regulated. Downregulation of BIM protected NB cells from the combination of perifosine/MK-2206 and ATXN3 downregulation. Downregulation of ATXN3 did not increase, but decrease the sensitivity of NB cells to etoposide/cisplatin, and knockdown of Bcl-xl attenuated this decrease in sensitivity.ConclusionDownregulation of ATXN3 enhanced AKT inhibitors (perifosine or MK-2206) induced cell death by BIM, but decreased the cell death induced by chemotherapeutic drugs (etoposide or cisplatin) via Bcl-xl. The expression of ATXN3 may be an indicator in selecting different treatment regimen.

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Section: Introductionmentioning

confidence: 99%

Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells

et al. 2021

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“…Cluster #133 relates proteins localized at the membrane with roles in intercellular signaling, development and organogenesis, as well as fatty acids transport proteins (Mahesh, 2013; Drazyk et al , 2019; Short et al , 2007, 1; Kim et al , 2020). AltProt IP_656413 associated with this cluster is coded by a pseudogene of the breakpoint cluster protein BCR, a Rho GTPase activating protein.…”

Section: Resultsmentioning

confidence: 99%

Newfound coding potential of transcripts unveils missing members of human protein communities

Leblanc

Brunet

Jacques

et al. 2020

Preprint

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Recent proteogenomic approaches have led to the discovery that regions of the transcriptome previously annotated as non-coding regions (i.e. UTRs, open reading frames overlapping annotated coding sequences in a different reading frame, and non-coding RNAs) frequently encode proteins (termed alternative proteins). This suggests that previously identified protein communities are partially incomplete since alternative proteins are not present in conventional protein databases. Here we incorporate this increased diversity in the re-analysis of a high throughput human network proteomics dataset thereby revealing the presence of 203 alternative proteins within 163 distinct communities associated with a wide variety of cellular functions and pathologies. We found 19 genes encoding both an annotated (reference) and an alternative protein interacting with each other. Of the 136 alternative proteins encoded by pseudogenes, 38 are direct interactors of reference proteins encoded by their respective parental gene. Finally, we experimentally validate several interactions involving alternative proteins. These data improve the blueprints of the human protein-protein interaction network and suggest functional roles for hundreds of alternative proteins.

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“…The gene signatures of circulating and BM PCs in cluster C3 were further compared and the few elevated genes in blood-derived cells are involved in the regulation of ER stress and autophagosome maturation (TMBIM6, UFD1, RBX1, GABARAP) or protection of stressed cells from apoptosis (TMBIM6, UFD1, DNAJB9) (Fig. 4e) [38][39][40][41]. It suggests that the aberrant PCs, when leaving the BM, may slightly alter their transcription profile for better survival in the microenvironment of peripheral blood.…”

Section: Comparison Of Plasma Cells Derived From the Bone Marrow And Peripheral Bloodmentioning

confidence: 99%

Transcriptional heterogeneity of clonal plasma cells and immune evasion in immunoglobulin light chain amyloidosis

Wang

Liu

et al. 2020

Int J Hematol

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Immunoglobulin light chain amyloidosis (AL amyloidosis) is characterized by the presence of B cells producing amyloidogenic immunoglobulin light chains (LCs). The low frequency of aberrant B cells in AL is often masked by a polyclonal B cell background, making it difficult for treatment. We analyzed the single-cell RNA sequencing data from GEO database to compare the plasma cell (PCs) in four individuals with AL amyloidosis, one AL subject after treatment, and six healthy controls. High interindividual variability in AL-derived PCs in their expression pattern of known overexpressed genes in multiple myeloma and their usage of V regions in LCs was demonstrated. We also found overexpression of MHC class I molecules as one of the common features of clonal PCs in individuals with AL amyloidosis. Significantly reduced frequencies of circulating natural killer (NK) cells were also observed in a small cohort of AL patients when compared to healthy controls. These data demonstrate that aberrant PCs in AL has a highly diverse transcriptome, an upregulation of MHC, and a dampened capability of immunosurveillance by reduction of circulating NK frequencies. The analysis of clonal PCs at single cell level may provide a better approach for precise molecular profiling and diagnosis of AL amyloidosis. Keywords Immunoglobulin light chain amyloidosis • Single-cell RNA sequencing • Plasma cells • Natural killer cells Abbreviations AL Immunoglobulin light chain BM Bone marrow DEG Differentially expressed gene ER Endoplasmic reticulum LC Light chain MGUS Monoclonal gammopathy of undetermined significance MM Multiple myeloma NK Natural killer PC Plasma cell scRNA-seq Single-cell RNA sequencing UMAP Uniform manifold approximation and projection Yujia Wang and Lushuang Xu have contributed equally to this work.

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TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

Cited by 40 publications

References 66 publications

Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells

Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells

Newfound coding potential of transcripts unveils missing members of human protein communities

Transcriptional heterogeneity of clonal plasma cells and immune evasion in immunoglobulin light chain amyloidosis

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