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1.
FEBS Open Bio ; 13(4): 655-669, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36734593

RESUMO

Ovarian cancer is characterized by a high degree of genetic heterogeneity. Platinum-based chemotherapy and some gene-targeted therapies have shown limited treatment efficacy due to toxicity and recurrence, and thus, it is essential to identify additional therapeutic targets based on an understanding of the pathological mechanism. Here, we report that endonuclease G, which exhibits altered expression in ovarian cancer, does not function as a cell death effector that digests chromosomal DNA in ovarian cancer. Endonuclease G is modulated by intracellular reactive oxygen species dynamics and plays a role in cell proliferation in ovarian cancer, suggesting that targeting endonuclease G alone or in combination with other antitumor agents may have the potential for development into a treatment for endonuclease G-overexpressing cancers, including ovarian cancer.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Endodesoxirribonucleases , Proliferação de Células/genética
2.
Biochem Biophys Res Commun ; 530(2): 440-447, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553630

RESUMO

C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that regulates many genes involved in normal cellular events. Because CtBP2 overexpression has been implicated in various human cancers, its protein levels must be precisely regulated. Previously, we reported that CtBP1 and CtBP1-mediated transcriptional repression are regulated by X-linked inhibitor of apoptosis protein (XIAP). In the present study, we sought to investigate whether CtBP2 is also regulated by XIAP or any other human IAP. We found that cIAP1 interacts with CtBP2 via through BIR domains to regulates the steady-state levels of CtBP2 protein in the nucleus. The levels of CtBP2 were gradually increased upon cIAP1 overexpression and downregulated upon cIAP1 depletion. Interestingly, the RING domain of cIAP1 responsible for E3 ligase activity was not required for this regulation. Finally, the levels of CtBP2 modulated by cIAP1 affected the transcription of CtBP2 target genes and subsequent cell migration. Taken together, our data demonstrate a novel function of cIAP1 which involves protecting CtBP2 from degradation to stabilize its steady-state level. These results suggest that cIAP1 might be a useful target in strategies aiming to downregulate the steady-state level of CtBP2 protein in treating human cancers.


Assuntos
Oxirredutases do Álcool/metabolismo , Proteínas Correpressoras/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Oxirredutases do Álcool/química , Linhagem Celular Tumoral , Proteínas Correpressoras/química , Células HeLa , Humanos , Proteínas Inibidoras de Apoptose/química , Neoplasias/metabolismo , Domínios e Motivos de Interação entre Proteínas , Mapas de Interação de Proteínas , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo
3.
Mol Cell ; 73(2): 364-376.e8, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30581142

RESUMO

Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating "bad sectors" in the mitochondrial network, serving as a mitochondrial quality surveillance system.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Mitofagia , Trifosfato de Adenosina/metabolismo , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Proteínas de Transporte de Cátions/genética , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Dinaminas , Metabolismo Energético , GTP Fosfo-Hidrolases/genética , Células HEK293 , Células HeLa , Humanos , Potencial da Membrana Mitocondrial , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Mutação , Neurônios/metabolismo , Neurônios/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Zinco/metabolismo
4.
Biochem Biophys Res Commun ; 506(3): 423-428, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30352681

RESUMO

The two major isoforms of the profilin (Pfn) family of proteins in mammals are Pfn1 and Pfn2. Pfn1 is a universal actin cytoskeletal regulator, while Pfn2 is an actin binding protein and mediator of synapse architecture, specific to neural tissues. However, it has recently been suggested that Pfn2 is also widely distributed in various tissues and involved in numerous cellular events as well as cytoskeletal regulation. In our previous study, we showed that Pfn1 is regulated by carboxyl terminus of Hsc70-Interacting Protein (CHIP) via an ubiquitin (Ub) proteasome system; although, the mechanism of regulation of Pfn2 is unknown. In this report, we demonstrate that Pfn2 is heavily ubiquitinated via differential Ub-linkages for degradation or as a regulatory signal. We also show that cellular inhibitor of apoptosis 1 (cIAP1) rather than CHIP, functions as an E3 ligase that targets Pfn2 for proteasomal degradation. Finally, we observed that Pfn2 levels, regulated by cIAP1, affected intracellular levels of reactive oxygen species. These results may provide a regulatory mechanism for cellular function of Pfn2 in various tissues.


Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Profilinas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Animais , Células HEK293 , Células HeLa , Humanos , Camundongos , Ligação Proteica , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
5.
Sci Rep ; 7(1): 9816, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28852129

RESUMO

eIF4E is an initiator protein in cap-dependent translation. Its overexpression is linked to tumorigenesis in various human cancers, suggesting that the levels of eIF4E must be under tight control in normal cells. Although several eIF4E regulatory mechanisms have been demonstrated, the intracellular mechanisms controlling eIF4E protein levels remain poorly understood. Here, we report that eIF4E is efficiently regulated by dual mechanisms, both involving human inhibitor of apoptosis family protein cIAP1. cIAP1 itself ubiquitinates eIF4E as an E3 ligase, and interestingly, cIAP1 also functions as a mediator to present eIF4E to another E3 ligase, CHIP. This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis. Our results provide the first evidence for a mediator function of cIAP1 and collaborative activity of cIAP1 and CHIP, suggesting that maintaining balanced levels of these E3 ligases might be beneficial for normal cell growth.


Assuntos
Fator de Iniciação 4E em Eucariotos/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/genética , Chaperonas Moleculares/metabolismo , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteólise
6.
Biochem Biophys Res Commun ; 451(4): 644-9, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25139236

RESUMO

Inhibitors of Apoptosis Proteins (IAPs) are evolutionarily well conserved and have been recognized as the key negative regulators of apoptosis. Recently, the role of IAPs as E3 ligases through the Ring domain was revealed. Using proteomic analysis to explore potential target proteins of DIAP1, we identified Drosophila Endonuclease G (dEndoG), which is known as an effector of caspase-independent cell death. In this study, we demonstrate that human EndoG interacts with IAPs, including human cellular Inhibitor of Apoptosis Protein 1 (cIAP1). EndoG was ubiquitinated by IAPs in vitro and in human cell lines. Interestingly, cIAP1 was capable of ubiquitinating EndoG in the presence of wild-type and mutant Ubiquitin, in which all lysines except K63 were mutated to arginine. cIAP1 expression did not change the half-life of EndoG and cIAP1 depletion did not alter its levels. Expression of dEndoG 54310, in which the mitochondrial localization sequence was deleted, led to cell death that could not be suppressed by DIAP1 in S2 cells. Moreover, EndoG-mediated cell death induced by oxidative stress in HeLa cells was not affected by cIAP1. Therefore, these results indicate that IAPs interact and ubiquitinate EndoG via K63-mediated isopeptide linkages without affecting EndoG levels and EndoG-mediated cell death, suggesting that EndoG ubiquitination by IAPs may serve as a regulatory signal independent of proteasomal degradation.


Assuntos
Morte Celular , Endodesoxirribonucleases/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Ubiquitinação , Animais , Apoptose , Drosophila , Proteínas de Drosophila/metabolismo , Células HEK293 , Células HeLa , Humanos , Estresse Oxidativo/fisiologia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
7.
Biochem Biophys Res Commun ; 446(4): 1060-6, 2014 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-24661873

RESUMO

Profilin1 (Pfn1) is a key mediator of actin polymerization and regulates cell migration. Low expression of Pfn1 is implicated in tumorigenesis of various cancers, including breast cancer. The regulatory mechanism behind Pfn1 levels has not yet been elucidated. In the present study, we find that Pfn1 is poly-ubiquitinated in human cell lines, and a portion of poly-ubiquitinated Pfn1 is regulated in a proteasome-dependent manner. C-terminus of Hsc70-interacting protein (CHIP), a co-chaperone E3 ligase, interacts with and ubiquitinates Pfn1, targeting it for proteasome-dependent degradation. Depletion of CHIP stabilizes Pfn1, suggesting that CHIP functions as a major E3 ligase for Pfn1. Stable expression of wild-type CHIP in the breast cancer cell line MDA-MB231 yielded downregulation of Pfn1 and enhanced cell migration. Pfn1 overexpression in MDA-MB231 cells expressing wild-type CHIP suppressed the enhanced cell migration. Taken together, our results demonstrate that CHIP regulates Pfn1 levels as an E3 ligase, and possibly plays a role in cell migration and metastasis of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Mama/patologia , Profilinas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Células HEK293 , Proteínas de Choque Térmico HSC70/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Mapas de Interação de Proteínas , Ubiquitina-Proteína Ligases/química , Ubiquitinação
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