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Title:
Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors | Nature Communications
Description:
MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies. MCL1, a pro-survival BCL-2 related protein with rapid turnover rate, is often dysregulated in cancers. Here, the authors show that MCL1โs stability is regulated by deubiquitinase USP13, and its inhibition sensitises tumor cells to BH3 mimetic inhibitors.
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nature portfolio research institute privacy policy advertising full size image shanghai institutions thermo scientific wnt/ฮฒ-catenin inhibitor c-82 growth media supplemented sirna library consisted reprints subcutaneously implanted tov-21g late-stage oral tumorigenesis cdk1-cyclin b1 initiates egfp-sgrna-f-caccggaagttcgagggcgacaccc egfp-sgrna-r-aaacgggtgtcgccctcgaacttcc library screen shanghai rising-star program usp13-null tov-21g cells short protein half-life huwe1-sgrna-1f-caccgacctgttggaccgcttcga huwe1-sgrna-1r-aaactcgaagcggtccaacaggtc huwe1-sgrna-2f-caccggaccgcttcgatggaatac huwe1-sgrna-2r-aaacgtattccatcgaagcggtcc nature 458 nature 545 nature 435 nature 538 nature 471 nature 463 nature 486 nature ubiquitin-specific protease usp28 social media amino-terminally truncated isoform potent small-molecule inhibitor anti-apoptotic mcl-1 localizes ubiquitin carboxyl-terminal hydrolases machadoโjoseph disease proteases mcl1-sgrna-1f-caccgcctcacgccagactcccgga mcl1-sgrna-1r-aaactccgggagtctggcgtgaggc mcl1-sgrna-2f-caccgtctcctcaagcggcgccgcg mcl1-sgrna-2r-aaaccgcggcgccgcttgaggagac pro-apoptotic bcl-2 proteins26 usp13-sgrna-1f-caccgttcctgcctccgctgccgcc usp13-sgrna-1r-aaacggcggcagcggaggcaggaac usp13-sgrna-2f-caccgacgcggatcgtgggcatgtg usp13-sgrna-2r-aaaccacatgcccacgatccgcgtc anti-apoptotic mcl-1 protein usp13-mcl1 regulatory axis
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description:MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies. MCL1, a pro-survival BCL-2 related protein with rapid turnover rate, is often dysregulated in cancers. Here, the authors show that MCL1รขยยs stability is regulated by deubiquitinase USP13, and its inhibition sensitises tumor cells to BH3 mimetic inhibitors.
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