Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as ...Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.展开更多
Abnormal protein expression or activities are associated with many diseases,especially cancer.Therefore,down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treat...Abnormal protein expression or activities are associated with many diseases,especially cancer.Therefore,down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treatment—a number of drugs based on proteolysis-targeting chimaera(PROTAC)mechanism have demonstrated clinical efficacy.Recent progress in the PROTAC strategy includes identification of the structure of the first ternary eutectic complex,extra-terminal domain-4-PROTAC-VonHippel-Lindau(BRD4-PROTAC-VHL),and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019.These discoveries strongly proved the value of the PROTAC strategy.In this review,we summarize recent meaningful research of PROTACs,including the molecular design and optimization strategy as well as clinical application of candidate molecules.We hope to provide useful insights for rational design of PROTACs.展开更多
Protein exerts a critical influence on the degradation behavior of absorbable magnesium(Mg)-based implants.However,the interaction mechanism between protein and a micro-arc oxidation(MAO)coating on Mg alloys remains u...Protein exerts a critical influence on the degradation behavior of absorbable magnesium(Mg)-based implants.However,the interaction mechanism between protein and a micro-arc oxidation(MAO)coating on Mg alloys remains unclear.Hereby,a MAO coating was fabricated on AZ31 Mg alloy.And its degradation behavior in phosphate buffer saline(PBS)containing bovine serum albumin(BSA)was investigated and compared with that of the uncoated alloy.Surface morphologies and chemical compositions were studied using Field-emission scanning electron microscope(FE-SEM),Fourier transform infrared spectrophotometer(FT-IR)and X-ray diffraction(XRD).The degradation behavior of the bare Mg alloy and its MAO coating was studied through electrochemical and hydrogen evolution tests.Cytotoxicity assay was applied to evaluate the biocompatibility of Mg alloy substrate and MAO coating.Results indicated that the presence of BSA decreased the degradation rate of Mg alloy substrate because BSA(RCH(NH2)COO‾)molecules combined with Mg2+ions to form(RCH(NH2)COO)2Mg and thus inhibited the dissolution of Mg(OH)2 by impeding the attack of Cl‾ions.In the case of MAO coated Mg alloy,the adsorption of BSA on MAO coating and the formation of(RCH(NH2)COO)2Mg exhibited a synergistic effect and enhanced the corrosion resistance of the coated alloy significantly.Furthermore,cell bioactive assay suggested that the MAO coating had good viability for MG63 cells due to its high surface area.展开更多
Ubiquitin-26S proteasome system （UPS） has been shown to play central roles in light and hormone-regulated plant growth and development. Previously, we have shown that MAX2, an F-box protein, positively regulates fac...Ubiquitin-26S proteasome system （UPS） has been shown to play central roles in light and hormone-regulated plant growth and development. Previously, we have shown that MAX2, an F-box protein, positively regulates facets of photomorphogenic development in response to light. However, how MAX2 controls these responses is still unknown. Here, we show that MAX2 oppositely regulates GA and ABA biosynthesis to optimize seed germination in response to light. Dose-response curves showed that max2 seeds are hyposensitive to GA and hypersensitive to ABA in seed ger- mination responses. RT-PCR assays demonstrated that the expression of GA biosynthetic genes is down-regulated, while the expression of GA catabolic genes is up-regulated in the rnax2 seeds compared to wild-type. Interestingly, expression of both ABA biosynthetic and catabolic genes is up-regulated in the max2 seeds compared to wild-type. Treatment with an auxin transport inhibitor, NPA, showed that increased auxin transport in max2 seedlings contributes to the long hypocotyl phenotype under light. Moreover, light-signaling phenotypes are restricted to max2, as the biosynthetic mutants in the strigolactone pathway, max1, max3, and rnax4, did not display any defects in seed germination and seedling de-etiolation compared to wild-type. Taken together, these data suggest that MAX2 modulates multiple hormone pathways to affect photomorphogenesis.展开更多
文摘Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
基金the support from grants(Nos.81573281)of National Natural Science Foundation of Chinasupport from Double First-Class initiative Innovation team project of China Pharmaceutical University(Nos.CPU2018GF11 and CPU2018GY34,China).
文摘Abnormal protein expression or activities are associated with many diseases,especially cancer.Therefore,down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treatment—a number of drugs based on proteolysis-targeting chimaera(PROTAC)mechanism have demonstrated clinical efficacy.Recent progress in the PROTAC strategy includes identification of the structure of the first ternary eutectic complex,extra-terminal domain-4-PROTAC-VonHippel-Lindau(BRD4-PROTAC-VHL),and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019.These discoveries strongly proved the value of the PROTAC strategy.In this review,we summarize recent meaningful research of PROTACs,including the molecular design and optimization strategy as well as clinical application of candidate molecules.We hope to provide useful insights for rational design of PROTACs.
基金supported by the National Natural Science Foundation of China(No.30771140)the Scientific Research Project of Educational Department of Henan ProvinceChina(No.13A310070)
基金supported by the National Natural Science Foundation of China(51571134)the SDUST Research Fund(2014TDJH104).
文摘Protein exerts a critical influence on the degradation behavior of absorbable magnesium(Mg)-based implants.However,the interaction mechanism between protein and a micro-arc oxidation(MAO)coating on Mg alloys remains unclear.Hereby,a MAO coating was fabricated on AZ31 Mg alloy.And its degradation behavior in phosphate buffer saline(PBS)containing bovine serum albumin(BSA)was investigated and compared with that of the uncoated alloy.Surface morphologies and chemical compositions were studied using Field-emission scanning electron microscope(FE-SEM),Fourier transform infrared spectrophotometer(FT-IR)and X-ray diffraction(XRD).The degradation behavior of the bare Mg alloy and its MAO coating was studied through electrochemical and hydrogen evolution tests.Cytotoxicity assay was applied to evaluate the biocompatibility of Mg alloy substrate and MAO coating.Results indicated that the presence of BSA decreased the degradation rate of Mg alloy substrate because BSA(RCH(NH2)COO‾)molecules combined with Mg2+ions to form(RCH(NH2)COO)2Mg and thus inhibited the dissolution of Mg(OH)2 by impeding the attack of Cl‾ions.In the case of MAO coated Mg alloy,the adsorption of BSA on MAO coating and the formation of(RCH(NH2)COO)2Mg exhibited a synergistic effect and enhanced the corrosion resistance of the coated alloy significantly.Furthermore,cell bioactive assay suggested that the MAO coating had good viability for MG63 cells due to its high surface area.
文摘Ubiquitin-26S proteasome system （UPS） has been shown to play central roles in light and hormone-regulated plant growth and development. Previously, we have shown that MAX2, an F-box protein, positively regulates facets of photomorphogenic development in response to light. However, how MAX2 controls these responses is still unknown. Here, we show that MAX2 oppositely regulates GA and ABA biosynthesis to optimize seed germination in response to light. Dose-response curves showed that max2 seeds are hyposensitive to GA and hypersensitive to ABA in seed ger- mination responses. RT-PCR assays demonstrated that the expression of GA biosynthetic genes is down-regulated, while the expression of GA catabolic genes is up-regulated in the rnax2 seeds compared to wild-type. Interestingly, expression of both ABA biosynthetic and catabolic genes is up-regulated in the max2 seeds compared to wild-type. Treatment with an auxin transport inhibitor, NPA, showed that increased auxin transport in max2 seedlings contributes to the long hypocotyl phenotype under light. Moreover, light-signaling phenotypes are restricted to max2, as the biosynthetic mutants in the strigolactone pathway, max1, max3, and rnax4, did not display any defects in seed germination and seedling de-etiolation compared to wild-type. Taken together, these data suggest that MAX2 modulates multiple hormone pathways to affect photomorphogenesis.
