Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Adicionar filtros








Intervalo de ano
1.
Protein & Cell ; (12): 42-54, 2015.
Artigo em Inglês | WPRIM | ID: wpr-757632

RESUMO

Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 (MYH9), heat shock cognate protein 70 (Hsc70), and dnaJ homolog subfamily A member 1 (DNAJA1), were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6-mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of protein acetylation with the capability of coordinating various cellular functions.


Assuntos
Animais , Camundongos , Acetilação , Actinas , Química , Metabolismo , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Proteínas de Choque Térmico HSC70 , Metabolismo , Proteínas de Choque Térmico HSP40 , Metabolismo , Desacetilase 6 de Histona , Histona Desacetilases , Metabolismo , Marcação por Isótopo , Fígado , Metabolismo , Lisina , Metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Miosina não Muscular Tipo IIA , Metabolismo , Ligação Proteica , Proteômica , Especificidade por Substrato , Espectrometria de Massas em Tandem
2.
Protein & Cell ; (12): 214-223, 2014.
Artigo em Inglês | WPRIM | ID: wpr-757533

RESUMO

Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.


Assuntos
Humanos , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Silenciamento de Genes , Desacetilase 6 de Histona , Histona Desacetilases , Metabolismo , Proteínas Associadas aos Microtúbulos , Metabolismo , Proteínas de Neoplasias , Metabolismo , Neoplasias Pancreáticas , Metabolismo , Patologia , Ligação Proteica
3.
Protein & Cell ; (12): 469-479, 2014.
Artigo em Inglês | WPRIM | ID: wpr-757485

RESUMO

Paclitaxel is a microtubule-targeting agent widely used for the treatment of many solid tumors. However, patients show variable sensitivity to this drug, and effective diagnostic tests predicting drug sensitivity remain to be investigated. Herein, we show that the expression of end-binding protein 1 (EB1), a regulator of microtubule dynamics involved in multiple cellular activities, in breast tumor tissues correlates with the pathological response of tumors to paclitaxel-based chemotherapy. In vitro cell proliferation assays reveal that EB1 stimulates paclitaxel sensitivity in breast cancer cell lines. Our data further demonstrate that EB1 increases the activity of paclitaxel to cause mitotic arrest and apoptosis in cancer cells. In addition, microtubule binding affinity analysis and polymerization/depolymerization assays show that EB1 enhances paclitaxel binding to microtubules and stimulates the ability of paclitaxel to promote microtubule assembly and stabilization. These findings thus reveal EB1 as a critical regulator of paclitaxel sensitivity and have important implications in breast cancer chemotherapy.


Assuntos
Feminino , Humanos , Antineoplásicos Fitogênicos , Farmacologia , Usos Terapêuticos , Apoptose , Neoplasias da Mama , Tratamento Farmacológico , Metabolismo , Patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Células MCF-7 , Proteínas Associadas aos Microtúbulos , Genética , Metabolismo , Microtúbulos , Química , Metabolismo , Paclitaxel , Farmacologia , Usos Terapêuticos , Interferência de RNA , RNA Interferente Pequeno , Metabolismo
4.
Protein & Cell ; (12): 266-276, 2013.
Artigo em Inglês | WPRIM | ID: wpr-757813

RESUMO

Angiogenesis, the expansion of preexisting blood vessels, is a complex process required for tumor growth and metastasis. Although current antiangiogenic strategies have shown promising results in several cancer types, identification of additional antiangiogenic targets is required to improve the therapeutic response. Herein, we show that the microtubule-binding protein CLIP-170 (cytoplasmic linker protein of 170 kDa) is highly expressed in breast tumor samples and correlates positively with blood vessel density. Depletion of CLIP-170 significantly impaired vascular endothelial tube formation and sprouting in vitro and inhibited breast tumor growth in mice by decreasing tumor vascularization. Our data further show that CLIP-170 is important for the migration but not the proliferation of vascular endothelial cells. In addition, CLIP-170 promotes the polarization of endothelial cells in response to the angiogenic stimulus. These findings thus demonstrate a critical role for CLIP-170 in tumor angiogenesis and suggest its potential as a novel antiangiogenic target.


Assuntos
Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama , Metabolismo , Patologia , Linhagem Celular Tumoral , Movimento Celular , Polaridade Celular , Células Endoteliais da Veia Umbilical Humana , Células MCF-7 , Camundongos Nus , Proteínas Associadas aos Microtúbulos , Genética , Metabolismo , Microtúbulos , Metabolismo , Proteínas de Neoplasias , Genética , Metabolismo , Neovascularização Patológica , Interferência de RNA , RNA Interferente Pequeno , Metabolismo , Transplante Heterólogo
5.
Protein & Cell ; (12): 150-160, 2011.
Artigo em Inglês | WPRIM | ID: wpr-757118

RESUMO

Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.


Assuntos
Animais , Embrião de Galinha , Humanos , Camundongos , Anilidas , Farmacologia , Movimento Celular , Polaridade Celular , Células Cultivadas , Galinhas , Células Endoteliais , Biologia Celular , Desacetilase 6 de Histona , Histona Desacetilases , Metabolismo , Fisiologia , Ácidos Hidroxâmicos , Farmacologia , Proteínas Associadas aos Microtúbulos , Metabolismo , Fisiologia , Neovascularização Fisiológica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA