Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by...Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.展开更多
Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death a...Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.展开更多
The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptoti...The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, respectively）. These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.展开更多
It has been shown that Bid and its truncated form tBid could induce cytochrome c (cyt c) release without impacting on PTP. We first show that Bid BH3 peptide, but not its mutant form of Bid BH3 peptide G94E, which is ...It has been shown that Bid and its truncated form tBid could induce cytochrome c (cyt c) release without impacting on PTP. We first show that Bid BH3 peptide, but not its mutant form of Bid BH3 peptide G94E, which is unable to bind to Bcl-xL, induces permeability transition pore (PTP) opening in a dose dependent manner. Bid BH3 peptide also induces the reduction of mitochondria membrane potential (Ψm) and cyt c release from mitochondrial in vitro. PTP opening and the loss of Ψm, were inhibited by Bcl-xL, cyclosporin A and ruthenium red, and the latter was an inhibitor of Ca2+ uniporter in the mitochondrial membrane. These results indicate that Bid BH3 peptide could antagonize Bcl-xL to induced PTP opening and mitochondrial dysfunction.展开更多
One group of Bcl-2 protein family,which shares only the BH3 domain(BH3-only),is critically involved in the regulation of programmed cell death.Herein we demonstrated a novel human BH3-only protein(designated as Bop)wh...One group of Bcl-2 protein family,which shares only the BH3 domain(BH3-only),is critically involved in the regulation of programmed cell death.Herein we demonstrated a novel human BH3-only protein(designated as Bop)which could induce apoptosis in a BH3 domain-dependent manner.Further analysis indicated that Bop mainly localized to mitochondria and used its BH3 domain to contact the loop regions of voltage dependent anion channel 1(VDAC1)in the outer mitochondrial membrane.In addition,purified Bop protein induced the loss of mitochondrial transmembrane potential(ΔΨm)and the release of cytochrome c.Furthermore,Bop used its BH3 domain to contact pro-survival Bcl-2 family members(Bcl-2,Bcl-XL,Mcl-1,A1 and Bcl-w),which could inhibit Bop-induced apoptosis.Bop would be constrained by pro-survival Bcl-2 proteins in resting cells,because Bop became released from phosphorylated Bcl-2 induced by microtubule-interfering agent like vincristine(VCR).Indeed,knockdown experiments indicated that Bop was partially required for VCR induced cell death.Finally,Bop might need to function through Bak and Bax,likely by releasing Bak from Bcl-XL sequestration.In conclusion,Bop may be a novel BH3-only factor that can engage with the regulatory network of Bcl-2 family members to process intrinsic apoptotic signaling.展开更多
The reduction of carboxamides into high value-added amines is a very interesting but great challenging topic.Herein we demonstrate that polynuclear lanthanide-oxo clusters Ln16(Ln=Eu and Gd)can be used as efficient ca...The reduction of carboxamides into high value-added amines is a very interesting but great challenging topic.Herein we demonstrate that polynuclear lanthanide-oxo clusters Ln16(Ln=Eu and Gd)can be used as efficient catalyst to reduce primary and secondary carboxamides to amines with excellent yield of 71%-98%and broad substrates scope.The methodology can extend to the gram-scale synthesis of phenethylamine drug with 93%yield.Based on the isolation and characterization of catalytic intermediates,a catalytic mechanism involving multipath reaction is proposed.This work provides efficient lanthanide cluster catalysts for the reduction of carboxamides to amines.展开更多
A research group led by Prof.Dai Wen from the Dalian Institute of Chemical Physics(DICP)of the Chinese Academy of Sciences(CAS)has realized borylation reactions involving N-heterocyclic carbene boranes(NHC-BH3)using a...A research group led by Prof.Dai Wen from the Dalian Institute of Chemical Physics(DICP)of the Chinese Academy of Sciences(CAS)has realized borylation reactions involving N-heterocyclic carbene boranes(NHC-BH3)using a simple and efficient heterogeneous photocatalytic system.This enables the synthesis of high-value transformations,including hydroboration and boron substitution products.展开更多
文摘Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.
文摘Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.
基金financially supported by Postdoctoral Applied Research Project of Qingdao(No.861605040085,to CZ,SW)Grant of Innovation Plan in Biomedical Research of Qingdao City(No.15-10-3-15-(28)-zch,to SW)
文摘The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, respectively）. These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.
基金This work was supported by "One-Hundred-Elite Plan" from the Chinese Academy of Sciences.
文摘It has been shown that Bid and its truncated form tBid could induce cytochrome c (cyt c) release without impacting on PTP. We first show that Bid BH3 peptide, but not its mutant form of Bid BH3 peptide G94E, which is unable to bind to Bcl-xL, induces permeability transition pore (PTP) opening in a dose dependent manner. Bid BH3 peptide also induces the reduction of mitochondria membrane potential (Ψm) and cyt c release from mitochondrial in vitro. PTP opening and the loss of Ψm, were inhibited by Bcl-xL, cyclosporin A and ruthenium red, and the latter was an inhibitor of Ca2+ uniporter in the mitochondrial membrane. These results indicate that Bid BH3 peptide could antagonize Bcl-xL to induced PTP opening and mitochondrial dysfunction.
基金supported in part by grants from the National Natural Science Foundation of China(Grant No.30600104)to H.T and(Grant No.31000403)to L.PMinistry of Science and Technology of China(No.2009CB522506)to H.T.and(No.2012CB518900)to L.P。
文摘One group of Bcl-2 protein family,which shares only the BH3 domain(BH3-only),is critically involved in the regulation of programmed cell death.Herein we demonstrated a novel human BH3-only protein(designated as Bop)which could induce apoptosis in a BH3 domain-dependent manner.Further analysis indicated that Bop mainly localized to mitochondria and used its BH3 domain to contact the loop regions of voltage dependent anion channel 1(VDAC1)in the outer mitochondrial membrane.In addition,purified Bop protein induced the loss of mitochondrial transmembrane potential(ΔΨm)and the release of cytochrome c.Furthermore,Bop used its BH3 domain to contact pro-survival Bcl-2 family members(Bcl-2,Bcl-XL,Mcl-1,A1 and Bcl-w),which could inhibit Bop-induced apoptosis.Bop would be constrained by pro-survival Bcl-2 proteins in resting cells,because Bop became released from phosphorylated Bcl-2 induced by microtubule-interfering agent like vincristine(VCR).Indeed,knockdown experiments indicated that Bop was partially required for VCR induced cell death.Finally,Bop might need to function through Bak and Bax,likely by releasing Bak from Bcl-XL sequestration.In conclusion,Bop may be a novel BH3-only factor that can engage with the regulatory network of Bcl-2 family members to process intrinsic apoptotic signaling.
基金supported by the National Natural Science Foundation of China(92161104,21871224,92161203,21721001)。
文摘The reduction of carboxamides into high value-added amines is a very interesting but great challenging topic.Herein we demonstrate that polynuclear lanthanide-oxo clusters Ln16(Ln=Eu and Gd)can be used as efficient catalyst to reduce primary and secondary carboxamides to amines with excellent yield of 71%-98%and broad substrates scope.The methodology can extend to the gram-scale synthesis of phenethylamine drug with 93%yield.Based on the isolation and characterization of catalytic intermediates,a catalytic mechanism involving multipath reaction is proposed.This work provides efficient lanthanide cluster catalysts for the reduction of carboxamides to amines.
文摘A research group led by Prof.Dai Wen from the Dalian Institute of Chemical Physics(DICP)of the Chinese Academy of Sciences(CAS)has realized borylation reactions involving N-heterocyclic carbene boranes(NHC-BH3)using a simple and efficient heterogeneous photocatalytic system.This enables the synthesis of high-value transformations,including hydroboration and boron substitution products.
