Dataset Information

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

ABSTRACT: Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms.

SUBMITTER: Fujita N

PROVIDER: S-EPMC5249261 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

Fujita Naonobu N Huang Wilson W Lin Tzu-Han TH Groulx Jean-Francois JF Jean Steve S Nguyen Jen J Kuchitsu Yoshihiko Y Koyama-Honda Ikuko I Mizushima Noboru N Fukuda Mitsunori M Kiger Amy A AA

eLife 20170107

Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling pr ...[more]

PMID: 28063257

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Project description:BACKGROUND:The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades. OBJECTIVE:To identify genes that influence cisplatin resistance in bladder cancer. DESIGN, SETTING, AND PARTICIPANTS:We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset. RESULTS AND LIMITATIONS:From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed. CONCLUSIONS:We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy. PATIENT SUMMARY:We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy.

Dataset Information

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

Publications

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

Similar Datasets

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