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Yi Sun - One of the best experts on this subject based on the ideXlab platform.
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DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mtorc1 2 signals
Oncogene, 2020Co-Authors: Xiaoyu Chen, Danrui Cui, Xiaoqing Dai, Longyuan Gong, Xiufang Xiong, Yi Sun, Fei Yang, Dongping Wei, Jianfeng ShuAbstract:The DEPTOR-mTORC1/2 axis has been shown to play an important, but a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings. The in vivo role of DEPTOR in tumorigenesis remains elusive. Here we showed that the levels of both DEPTOR protein and mRNA were substantially decreased in human prostate cancer tissues, which positively correlated with disease progression. DEPTOR depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, DEPTOR depletion not only activated both mTORC1 and mTORC2 signals to promote cell proliferation and survival, but also induced an AKT-dependent epithelial-mesenchymal transition (EMT) and β-catenin nuclear translocation to promote cell migration and invasion. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion. Importantly, in a DEPTOR-KO mouse model, DEPTOR knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of mTOR signaling. Collectively, our study demonstrates that DEPTOR is a tumor suppressor in the prostate, and its depletion promotes tumorigenesis via the activation of mTORC1 and mTORC2 signals. Thus, DEPTOR reactivation via a variety of means would have therapeutic potential for the treatment of prostate cancer.
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Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.
Cell death & disease, 2018Co-Authors: Xiufang Xiong, Yi Sun, Xia Liu, Yongchao ZhaoAbstract:RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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DEPTOR has growth suppression activity against pancreatic cancer cells
Oncotarget, 2014Co-Authors: G. Sun, Yongchao Zhao, Dafydd G. Thomas, Joel K. Greenson, Mark M. Zalupski, Edgar Ben-josef, Yi SunAbstract:// Hua Li 1 , Grace Y. Sun 1 , Yongchao Zhao 1 , Dafydd Thomas 2 , Joel K. Greenson 2 , Mark M. Zalupski 3 , Edgar Ben-Josef 1 , Yi Sun 1, 4 1 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA 2 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA 4 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China Correspondence to: Yi Sun, email: sunyi@umich.edu or yisun@zju.edu.cn Keywords: DEPTOR, mTOR pathway, pancreatic cancer, growth suppression Received: August 26, 2014 Accepted: October 27, 2014 Published: December 30, 2014 ABSTRACT DEPTOR was reported as a naturally occurring inhibitor of mTORC1 and mTORC2. The role of DEPTOR in the growth and survival of pancreatic cancer cells has not previously been determined. Here we report that while DEPTOR shows a cytoplasmic expression in both normal pancreatic acinar and islet cells in a patchy manner, its expression is reduced in PanIN1 and PanIN2 and completely lost in 100 out of 101 pancreatic ductal adenocarcinoma (PDAC) tissues. Ectopic DEPTOR expression in two pancreatic cancer cell lines, Panc-1 and Miapaca-2, caused a significant 1) suppression of anchorage-dependent growth in monolayer culture, particularly under conditions with growth factor deprivation; 2) decreased clonogenic survival, and 3) suppressed anchorage-independent growth in soft agar. These effects are attributable to moderate induction of apoptosis and growth arrest at the S and G2/M phases, in a cell line dependent manner. Furthermore, ectopic DEPTOR expression moderately inhibited mTORC1 activity, as demonstrated by reduced phosphorylation of S6K, S6, and 4E-BP1. Taken together, these data suggest that DEPTOR has a tumor suppressive activity against pancreatic cancer cells, and its loss of expression may contribute to pancreatic tumorigenesis.
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Abstract 4160: DEPTOR, an mTOR inhibitor, is a novel substrate of SCFαTrCP E3 ubiquitin ligase upon S6K1/RSK1 phosphorylation and regulates survival and autophagy
Molecular and Cellular Biology, 2012Co-Authors: Yongchao Zhao, Xiufang Xiong, Yi SunAbstract:DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4160. doi:1538-7445.AM2012-4160
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abstract 4160 DEPTOR an mtor inhibitor is a novel substrate of scfαtrcp e3 ubiquitin ligase upon s6k1 rsk1 phosphorylation and regulates survival and autophagy
Cancer Research, 2012Co-Authors: Yongchao Zhao, Xiufang Xiong, Yi SunAbstract:DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4160. doi:1538-7445.AM2012-4160
Yongchao Zhao - One of the best experts on this subject based on the ideXlab platform.
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DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity.
Cell death & disease, 2020Co-Authors: Danrui Cui, Xiaoqing Dai, Longyuan Gong, Xiaoyu Chen, Linchen Wang, Xiufang Xiong, Yongchao ZhaoAbstract:DEP-domain containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, has essential roles in several processes, including cell growth, metabolism, apoptosis, and immunity. DEPTOR expression has been shown to be diversely controlled at transcriptional levels in cell- and context-specific manners. However, whether there is a general mechanism for the regulation of DEPTOR expression remains largely unknown. Here, we report that DEPTOR is a downstream target of the tumor suppressor, p53, whose activity is positively correlated with DEPTOR expression both in vitro in cell cultures and in vivo in mouse tissues. Mechanistically, p53 directly binds to the DEPTOR promoter and transactivates its expression. Depletion of the p53-binding site on the DEPTOR promoter by CRISPR-Cas9 technology decreases DEPTOR expression and promotes cell proliferation and survival by activating AKT signaling. Importantly, inhibition of AKT by small molecular inhibitors or genetic knockdown abrogates the induction of cell growth and survival induced by deletion of the p53-binding region on the DEPTOR promoter. Furthermore, p53, upon activation by the genotoxic agent doxorubicin, induces DEPTOR expression, leading to cancer cell resistance to doxorubicin. Together, DEPTOR is a direct p53 downstream target and contributes to p53-mediated inhibition of cell proliferation, survival, and chemosensitivity.
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Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.
Cell death & disease, 2018Co-Authors: Xiufang Xiong, Yi Sun, Xia Liu, Yongchao ZhaoAbstract:RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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DEPTOR has growth suppression activity against pancreatic cancer cells
Oncotarget, 2014Co-Authors: G. Sun, Yongchao Zhao, Dafydd G. Thomas, Joel K. Greenson, Mark M. Zalupski, Edgar Ben-josef, Yi SunAbstract:// Hua Li 1 , Grace Y. Sun 1 , Yongchao Zhao 1 , Dafydd Thomas 2 , Joel K. Greenson 2 , Mark M. Zalupski 3 , Edgar Ben-Josef 1 , Yi Sun 1, 4 1 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA 2 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA 4 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China Correspondence to: Yi Sun, email: sunyi@umich.edu or yisun@zju.edu.cn Keywords: DEPTOR, mTOR pathway, pancreatic cancer, growth suppression Received: August 26, 2014 Accepted: October 27, 2014 Published: December 30, 2014 ABSTRACT DEPTOR was reported as a naturally occurring inhibitor of mTORC1 and mTORC2. The role of DEPTOR in the growth and survival of pancreatic cancer cells has not previously been determined. Here we report that while DEPTOR shows a cytoplasmic expression in both normal pancreatic acinar and islet cells in a patchy manner, its expression is reduced in PanIN1 and PanIN2 and completely lost in 100 out of 101 pancreatic ductal adenocarcinoma (PDAC) tissues. Ectopic DEPTOR expression in two pancreatic cancer cell lines, Panc-1 and Miapaca-2, caused a significant 1) suppression of anchorage-dependent growth in monolayer culture, particularly under conditions with growth factor deprivation; 2) decreased clonogenic survival, and 3) suppressed anchorage-independent growth in soft agar. These effects are attributable to moderate induction of apoptosis and growth arrest at the S and G2/M phases, in a cell line dependent manner. Furthermore, ectopic DEPTOR expression moderately inhibited mTORC1 activity, as demonstrated by reduced phosphorylation of S6K, S6, and 4E-BP1. Taken together, these data suggest that DEPTOR has a tumor suppressive activity against pancreatic cancer cells, and its loss of expression may contribute to pancreatic tumorigenesis.
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Abstract 4160: DEPTOR, an mTOR inhibitor, is a novel substrate of SCFαTrCP E3 ubiquitin ligase upon S6K1/RSK1 phosphorylation and regulates survival and autophagy
Molecular and Cellular Biology, 2012Co-Authors: Yongchao Zhao, Xiufang Xiong, Yi SunAbstract:DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4160. doi:1538-7445.AM2012-4160
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abstract 4160 DEPTOR an mtor inhibitor is a novel substrate of scfαtrcp e3 ubiquitin ligase upon s6k1 rsk1 phosphorylation and regulates survival and autophagy
Cancer Research, 2012Co-Authors: Yongchao Zhao, Xiufang Xiong, Yi SunAbstract:DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4160. doi:1538-7445.AM2012-4160
Xiufang Xiong - One of the best experts on this subject based on the ideXlab platform.
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DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity.
Cell death & disease, 2020Co-Authors: Danrui Cui, Xiaoqing Dai, Longyuan Gong, Xiaoyu Chen, Linchen Wang, Xiufang Xiong, Yongchao ZhaoAbstract:DEP-domain containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, has essential roles in several processes, including cell growth, metabolism, apoptosis, and immunity. DEPTOR expression has been shown to be diversely controlled at transcriptional levels in cell- and context-specific manners. However, whether there is a general mechanism for the regulation of DEPTOR expression remains largely unknown. Here, we report that DEPTOR is a downstream target of the tumor suppressor, p53, whose activity is positively correlated with DEPTOR expression both in vitro in cell cultures and in vivo in mouse tissues. Mechanistically, p53 directly binds to the DEPTOR promoter and transactivates its expression. Depletion of the p53-binding site on the DEPTOR promoter by CRISPR-Cas9 technology decreases DEPTOR expression and promotes cell proliferation and survival by activating AKT signaling. Importantly, inhibition of AKT by small molecular inhibitors or genetic knockdown abrogates the induction of cell growth and survival induced by deletion of the p53-binding region on the DEPTOR promoter. Furthermore, p53, upon activation by the genotoxic agent doxorubicin, induces DEPTOR expression, leading to cancer cell resistance to doxorubicin. Together, DEPTOR is a direct p53 downstream target and contributes to p53-mediated inhibition of cell proliferation, survival, and chemosensitivity.
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DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mtorc1 2 signals
Oncogene, 2020Co-Authors: Xiaoyu Chen, Danrui Cui, Xiaoqing Dai, Longyuan Gong, Xiufang Xiong, Yi Sun, Fei Yang, Dongping Wei, Jianfeng ShuAbstract:The DEPTOR-mTORC1/2 axis has been shown to play an important, but a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings. The in vivo role of DEPTOR in tumorigenesis remains elusive. Here we showed that the levels of both DEPTOR protein and mRNA were substantially decreased in human prostate cancer tissues, which positively correlated with disease progression. DEPTOR depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, DEPTOR depletion not only activated both mTORC1 and mTORC2 signals to promote cell proliferation and survival, but also induced an AKT-dependent epithelial-mesenchymal transition (EMT) and β-catenin nuclear translocation to promote cell migration and invasion. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion. Importantly, in a DEPTOR-KO mouse model, DEPTOR knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of mTOR signaling. Collectively, our study demonstrates that DEPTOR is a tumor suppressor in the prostate, and its depletion promotes tumorigenesis via the activation of mTORC1 and mTORC2 signals. Thus, DEPTOR reactivation via a variety of means would have therapeutic potential for the treatment of prostate cancer.
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DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals.
Oncogene, 2019Co-Authors: Xiaoyu Chen, Danrui Cui, Xiaoqing Dai, Xiufang Xiong, Fei Yang, Dongping Wei, Jianfeng Shu, Longyuan GongAbstract:The DEPTOR-mTORC1/2 axis has been shown to play an important, but a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings. The in vivo role of DEPTOR in tumorigenesis remains elusive. Here we showed that the levels of both DEPTOR protein and mRNA were substantially decreased in human prostate cancer tissues, which positively correlated with disease progression. DEPTOR depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, DEPTOR depletion not only activated both mTORC1 and mTORC2 signals to promote cell proliferation and survival, but also induced an AKT-dependent epithelial-mesenchymal transition (EMT) and β-catenin nuclear translocation to promote cell migration and invasion. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion. Importantly, in a DEPTOR-KO mouse model, DEPTOR knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of mTOR signaling. Collectively, our study demonstrates that DEPTOR is a tumor suppressor in the prostate, and its depletion promotes tumorigenesis via the activation of mTORC1 and mTORC2 signals. Thus, DEPTOR reactivation via a variety of means would have therapeutic potential for the treatment of prostate cancer.
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Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.
Cell death & disease, 2018Co-Authors: Xiufang Xiong, Yi Sun, Xia Liu, Yongchao ZhaoAbstract:RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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Abstract 4160: DEPTOR, an mTOR inhibitor, is a novel substrate of SCFαTrCP E3 ubiquitin ligase upon S6K1/RSK1 phosphorylation and regulates survival and autophagy
Molecular and Cellular Biology, 2012Co-Authors: Yongchao Zhao, Xiufang Xiong, Yi SunAbstract:DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4160. doi:1538-7445.AM2012-4160
Eun Y. Lee - One of the best experts on this subject based on the ideXlab platform.
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DEPTOR is a novel target of wnt β catenin c myc and contributes to colorectal cancer cell growth
Cancer Research, 2018Co-Authors: Qingding Wang, Yuning Zhou, Piotr G. Rychahou, Jennifer W. Harris, Yekaterina Y. Zaytseva, Jinpeng Liu, Chi Wang, Heidi L. Weiss, Chunming Liu, Eun Y. LeeAbstract:Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer (CRC) growth by deregulating expression of downstream target genes including the c-Myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in CRC have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to CRC growth and metastasis. Here we show that DEPTOR, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in CRC cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased, the expression of DEPTOR. c-Myc bound the promoter of DEPTOR and transcriptionally regulated DEPTOR expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of CRC cell growth in vitro and in vivo. DEPTOR expression was increased in CRC cells; knockdown of DEPTOR induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in CRC cell lines and primary human CRC cells. Importantly, our work identifies DEPTOR as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in CRC cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating CRC with elevated c-Myc.
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DEPTOR Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth
Cancer research, 2018Co-Authors: Qingding Wang, Yuning Zhou, Piotr G. Rychahou, Jennifer W. Harris, Yekaterina Y. Zaytseva, Jinpeng Liu, Chi Wang, Heidi L. Weiss, Chunming Liu, Eun Y. LeeAbstract:Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer (CRC) growth by deregulating expression of downstream target genes including the c-Myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in CRC have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to CRC growth and metastasis. Here we show that DEPTOR, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in CRC cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased, the expression of DEPTOR. c-Myc bound the promoter of DEPTOR and transcriptionally regulated DEPTOR expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of CRC cell growth in vitro and in vivo. DEPTOR expression was increased in CRC cells; knockdown of DEPTOR induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in CRC cell lines and primary human CRC cells. Importantly, our work identifies DEPTOR as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in CRC cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating CRC with elevated c-Myc.
Jiandie D. Lin - One of the best experts on this subject based on the ideXlab platform.
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the baf60c DEPTOR pathway links skeletal muscle inflammation to glucose homeostasis in obesity
Diabetes, 2014Co-Authors: Zhuo Xian Meng, Lin Wang, Yuanyuan Xiao, Jiandie D. LinAbstract:Skeletal muscle insulin resistance in type 2 diabetes is associated with a shift from oxidative to glycolytic metabolism in myofibers. However, whether this metabolic switch is detrimental or adaptive for metabolic homeostasis has not been resolved. We recently demonstrated that the Baf60c/DEPTOR pathway promotes glycolytic metabolism in the muscle and protects mice from diet-induced insulin resistance. However, the nature of the signals that impinge on this pathway and the role of Baf60c in glucose homeostasis in the severe insulin-resistant state remain unknown. Here we show that expression of Baf60c and DEPTOR was downregulated in skeletal muscle in obesity, accompanied by extracellular signal–related kinase (ERK) activation. In cultured myotubes, inhibition of ERK, but not Jun NH2-terminal kinase and IκB kinase, blocked the downregulation of Baf60c and DEPTOR by the proinflammatory cytokine tumor necrosis factor-α. Treatment of obese mice with the ERK inhibitor U0126 rescued Baf60c and DEPTOR expression in skeletal muscle and lowered blood glucose. Transgenic rescue of Baf60c in skeletal muscle restored DEPTOR expression and Akt phosphorylation and ameliorated insulin resistance in ob/ob mice. This study identifies the Baf60c/DEPTOR pathway as a target of proinflammatory signaling in skeletal muscle that may link meta-inflammation to skeletal myofiber metabolism and insulin resistance.
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The Baf60c/DEPTOR Pathway Links Skeletal Muscle Inflammation to Glucose Homeostasis in Obesity
Diabetes, 2014Co-Authors: Zhuo Xian Meng, Lin Wang, Yuanyuan Xiao, Jiandie D. LinAbstract:Skeletal muscle insulin resistance in type 2 diabetes is associated with a shift from oxidative to glycolytic metabolism in myofibers. However, whether this metabolic switch is detrimental or adaptive for metabolic homeostasis has not been resolved. We recently demonstrated that the Baf60c/DEPTOR pathway promotes glycolytic metabolism in the muscle and protects mice from diet-induced insulin resistance. However, the nature of the signals that impinge on this pathway and the role of Baf60c in glucose homeostasis in the severe insulin-resistant state remain unknown. Here we show that expression of Baf60c and DEPTOR was downregulated in skeletal muscle in obesity, accompanied by extracellular signal–related kinase (ERK) activation. In cultured myotubes, inhibition of ERK, but not Jun NH2-terminal kinase and IκB kinase, blocked the downregulation of Baf60c and DEPTOR by the proinflammatory cytokine tumor necrosis factor-α. Treatment of obese mice with the ERK inhibitor U0126 rescued Baf60c and DEPTOR expression in skeletal muscle and lowered blood glucose. Transgenic rescue of Baf60c in skeletal muscle restored DEPTOR expression and Akt phosphorylation and ameliorated insulin resistance in ob/ob mice. This study identifies the Baf60c/DEPTOR pathway as a target of proinflammatory signaling in skeletal muscle that may link meta-inflammation to skeletal myofiber metabolism and insulin resistance.