Rictor Regulates Global Phosphorylation Dynamics in Renal Cancer Cells in Response to Irradiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Ruibing Chen
PROVIDER: PXD065189 | iProX | Thu Jun 19 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage.
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2009-11-25 | GSE19130 | GEO
Project description:The study comprises various components: We aim to screen out different gene expression profile in acute rejection on the kidney. We aim to screen out different gene expression profile in acute tubular necrosis on the kidney. We aim to screen out different gene expression profile in borderline change on the kidney. We aim to screen out different gene expression profile in non-rejection on the kidney. We aim to screen out different gene expression profile in presumed rejection on the kidney. We aim to screen out different gene expression profile in renal recipients with stable function. Results from the various study components can help to diagnose renal allograft dysfunction with different causes by distinct gene expression profile. Keywords: acute rejection, acute tubular necrosis, borderline change, non-rejection, presumed rejection, renal recipients with stable function, Samples GSM456771-GSM456800: This study has been accomplished with 15 patients of acute rejection on the kidney.Technical replicates: 2 replicates(except AR10 and AR13) Samples GSM456801-GSM456810: This study has been accomplished with 5 patients of acute tubular necrosis on the kidney. Technical replicates: 2 replicates(except ATN4) Samples GSM456811-GSM456831: This study has been accomplished with 11 patients of borderline change on the kidney.Tecnical replicates:2 replicates(except BL8 and BL11) Samples GSM456833-GSM456850: This study has been accomplished with 9 patients of non-rejection on the kidney.Technical replicates: 2 replicates Samples GSM456851-GSM456864: This study has been accomplished with 7 patients of presumed rejection on the kidney.Technical replicates: 2 replicates Samples GSM456865-GSM456894: This study has been accomplished with 15 patients of renal recipients with stable function.Technical replicates: 2 replicates
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Project description:mTOR is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of this pathway promotes tumor growth and metastasis and drives tumor resistance to chemotherapy and cancer drugs, making mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer, however, the basis for drug sensitivity remains poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity, uncovered USP9X deubiquitinase as the only mutated gene shared by the tumors. The clonal characteristics of the mutations, revealed by studying multiple patients’ primary and metastatic samples along the years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X depleted HeLa and renal cancer 786-O cells and the pharmacological inhibition of USP9X, confirmed a crucial role of this protein in the patients’ sensitivity to mTOR inhibition. As no direct effect of USP9X in mTORC1 was detected, we performed ubiquitylome analyses that identified p62 as a direct USP9X target. Increased p62 ubiquitination and an augmented rapamycin effect upon bortezomib treatment, together with p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X depleted cells can synergize with mTOR inhibitors. In summary, here we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients and represents a clinically exploitable strategy that could increase sensitivity to these drugs
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