The Experts below are selected from a list of 40041 Experts worldwide ranked by ideXlab platform
Judit Ovádi - One of the best experts on this subject based on the ideXlab platform.
-
tppp p25 promotes tubulin acetylation by inhibiting Histone Deacetylase 6
Journal of Biological Chemistry, 2010Co-Authors: Natália Tokési, Attila Lehotzky, Istvan Horvath, Bálint Szabó, Judit Oláh, Pierre Lau, Judit OvádiAbstract:TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of α-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of α-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (Histone Deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the Deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 μm concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization.
-
TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6
The Journal of biological chemistry, 2010Co-Authors: Natália Tokési, Attila Lehotzky, Istvan Horvath, Bálint Szabó, Judit Oláh, Pierre Lau, Judit OvádiAbstract:TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of α-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of α-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (Histone Deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the Deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 μm concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization.
Weiping Tang - One of the best experts on this subject based on the ideXlab platform.
-
Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
ACS medicinal chemistry letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
-
development of selective Histone Deacetylase 6 hdac6 degraders recruiting von hippel lindau vhl e3 ubiquitin ligase
ACS Medicinal Chemistry Letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
Ka Yang - One of the best experts on this subject based on the ideXlab platform.
-
Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
ACS medicinal chemistry letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
-
development of selective Histone Deacetylase 6 hdac6 degraders recruiting von hippel lindau vhl e3 ubiquitin ligase
ACS Medicinal Chemistry Letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
-
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity.
Journal of medicinal chemistry, 2019Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Zora Novakova, Haibo Xie, Jin Liu, Kerry A. Smith, Cyril BarinkaAbstract:Histone Deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.
Natália Tokési - One of the best experts on this subject based on the ideXlab platform.
-
tppp p25 promotes tubulin acetylation by inhibiting Histone Deacetylase 6
Journal of Biological Chemistry, 2010Co-Authors: Natália Tokési, Attila Lehotzky, Istvan Horvath, Bálint Szabó, Judit Oláh, Pierre Lau, Judit OvádiAbstract:TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of α-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of α-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (Histone Deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the Deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 μm concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization.
-
TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6
The Journal of biological chemistry, 2010Co-Authors: Natália Tokési, Attila Lehotzky, Istvan Horvath, Bálint Szabó, Judit Oláh, Pierre Lau, Judit OvádiAbstract:TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of α-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of α-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (Histone Deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the Deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 μm concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization.
Eric D Leisten - One of the best experts on this subject based on the ideXlab platform.
-
Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
ACS medicinal chemistry letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
-
development of selective Histone Deacetylase 6 hdac6 degraders recruiting von hippel lindau vhl e3 ubiquitin ligase
ACS Medicinal Chemistry Letters, 2020Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Xueqing Nie, Binkai Liu, Zhi Wen, Jing Zhang, Michael D Cunningham, Weiping TangAbstract:Histone Deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed a...
-
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity.
Journal of medicinal chemistry, 2019Co-Authors: Ka Yang, Zhongrui Zhang, Eric D Leisten, Zora Novakova, Haibo Xie, Jin Liu, Kerry A. Smith, Cyril BarinkaAbstract:Histone Deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.