Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively is able to increase apoptosis in cancer cells as agent with minimum toxicity to noncancerous cells. However, all cancer cells are not sensitive to TRAIL-induced apoptosis. In this study, we showed the sub-lethal concentrations of a lysosomotropic autophagy inhibitor, IITZ-01, sensitizes cancer cells (renal, lung, and breast carcinoma) to TRAIL-induced apoptosis through DR5 upregulation and survivin downregulation through ubiquitin-proteasome pathway. Knockdown of DR5 or overexpression of survivin inhibited combined treatment with IITZ-01 and TRAIL-induced apoptosis. IITZ-01 downregulated protein expression of Cbl, ubiquitin E3 ligase, and decreased expression level of Cbl markedly led to increase DR5 protein expression and TRAIL sensitivity. Moreover, IITZ-01 decreased expression level of survivin protein via downregulation of deubiquitinase ubiquitin-specific protease 9X (USP9X) expression. Taken together, these results provide the first evidence that IITZ-01 enhances TRAIL-mediated apoptosis through DR5 stabilization by downregulation of Cbl and USP9X-dependent survivin ubiquitination and degradation in renal carcinoma cells.
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PMID:Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway. 3282 66

Recent studies have revealed that ARHGEF7 is upregulated in many malignant tumors, but the underlying molecular mechanisms to this response remain to be fully elucidated. In this study, we confirm that ARHGEF7 physically interacts with KLHL2, which was previously identified to be an E3 ubiquitin ligase. KLHL2 is capable of promoting ARHGEF7 degradation via the ubiquitin-proteasome pathway. We identify that the Kelch domain of KLHL2 is necessary for binding with ARHGEF7 and downstream activities. In addition, we find that ARHGEF7 is overexpressed in clear cell renal cell carcinoma (ccRCC) specimens, and that the level of expression negatively correlates with that of KLHL2. Moreover, we utilize knockdown loss-of-function assays to demonstrate that ARHGEF7 in 786-O and A498 cell lines can act as a regulator of cell proliferation, migration and invasion, and that these effects can be reversed by KLHL2 inactivation. Taken together, our data suggest that ARHGEF7 is a putative oncogene that functions via an interaction with KLHL2, and control of ARHGEF7 can be a potential future target to inhibit tumor progression.
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PMID:Ubiquitin ligase KLHL2 promotes the degradation and ubiquitination of ARHGEF7 protein to suppress renal cell carcinoma progression. 3316 74


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