ShRNA TMEM258 knockdown in HeLa
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89542 | GEO | 2016/11/05
SECONDARY ACCESSION(S): PRJNA352509
REPOSITORIES: GEO
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Project description:To understand how OMA1 affects mitochondrial proteostasis and stress responses, we performed a proteomic survey of OMA1-deficient cells for proteolytic substrates. We demonstrate that OMA1 cleaves the mitochondrial chaperone DNAJC15 facilitating its degradation by the mitochondrial m-AAA protease. The loss of DNAJC15 alters protein import by TIM23 protein translocases in the IM and limits the accumulation of OXPHOS-related mitochondrial matrix and IM proteins. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum (ER) and trigger an ATF6-related unfolded protein response. These results demonstrate that OMA1 allows to adapt mitochondrial protein biogenesis to stress and reveal an intricate network of cellular stress responses to proteostasis disturbances.
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Project description:The majority of secretory proteins undergo N-glycosylation, a process catalyzed by oligosaccharyltransferase (OST), a membrane-bound protein complex that associates with the translocation channels within the endoplasmic reticulum (ER). Proteins failing quality control undergo ER-associated degradation (ERAD) by retrotranslocation to cytosolic proteasomes. Using a misfolded protein bait and SILAC proteomics, we unexpectedly identified several OST subunits among top hits. For further details, Please refer to the publication "Oligosaccharyltransferase is involved in targeting to ER-associated degradation" by Marina Shenkman et al..
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Project description:Multiple myeloma (MM) is an incurable malignancy characterized by mutated plasma cell clonal expansion in the bone marrow, leading to severe clinical symptoms. Thus, identifying new therapeutic targets for MM is crucial. We identified the oligosaccharyltransferase (OST) complex as a novel vulnerability in MM cells. Elevated expression of this complex is associated with relapsed, high-risk MM, and poor prognosis. Disrupting the OST complex suppressed MM cell growth, inducing cell cycle arrest and apoptosis. Combined inhibition with bortezomib synergistically eliminated MM cells in vitro and in vivo, via suppressing genes related to bortezomib-resistant phenotypes. Mechanistically, OST complex disruption downregulated pathological gene signatures (NF-kB signaling, mTORC1 pathway, glycolysis, MYC targets, and cell cycle), induced TRAIL-mediated apoptosis and inflammatory pathways. MYC translation was robustly suppressed upon inhibiting the OST complex. Collectively, the OST complex presents a novel target for MM treatment, and combining its inhibition with bortezomib offers a promising approach for relapsed MM patients.
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2010-04-08 | E-GEOD-19519 | biostudies-arrayexpress
Project description:The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called “ER stress” which induces the unfolded protein response (UPR) which is a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B-cells and then measured gene expression at 10 time-points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in ER stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE which showed significant increase in expression following ER stress in B-cells and in primary fibroblasts. To study the links between unfolded protein response and disease susceptibility, we identified ER stress responsive genes that are associated with human diseases and assessed individual differences in ER stress response. Many of the UPR genes are associated with Mendelian disorders such as Wolfram syndrome and complex human diseases including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility. Keywords: array-based gene expression
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Project description:Oncogenic signaling promotes tumor invasion and metastasis, in part, by increasing the expression of tri- and tetra- branched N-glycans. The branched N-glycans bind to galectins forming a multivalent lattice that enhances cell surface residency of growth factor receptors, and focal adhesion turnover. N-acetylglucosaminyltransferase I (MGAT1), the first branching enzyme in the pathway, is required for the addition of all subsequent branches. Here we have introduced MGAT1 shRNA into human HeLa cervical and PC-3-Yellow prostate tumor cells lines, generating cell lines with reduced transcript, enzyme activity and branched N-glycans at the cell surface. MGAT1 knockdown inhibited HeLa cell migration and invasion, but did not alter cell proliferation rates. Swainsonine, an inhibitor of α-mannosidase II immediately downstream of MGAT1, also inhibited cell invasion and was not additive with MGAT1 shRNA, consistent with a common mechanism of action. Focal adhesion and microfilament organization in MGAT1 knockdown cells also indicate a less motile phenotype. In vivo, MGAT1 knockdown in the PC-3-Yellow orthotopic prostate cancer xenograft model significantly decreased primary tumor growth and the incidence of lung metastases. Our results demonstrate that blocking MGAT1 is a potential target for anti-cancer therapy.
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