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1.
Int J Cancer ; 144(3): 558-568, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30230528

RESUMO

Androgen receptor (AR) signaling is involved in the initiation and progression of prostate cancer (PCa), which is the most frequently diagnosed nonskin cancer and remains a leading cause of cancer-related death in men. Further investigation of the involvement of AR signaling in PCa progression is urgently needed. In the present study, we performed a yeast two-hybrid screen and demonstrated that SERTA domain-containing protein 1 (Sertad1) is a novel AR-binding protein that binds to the AR ligand binding domain (LBD). The binding between AR-LBD and Sertad1 was confirmed by glutathione S-transferase (GST) pull-down assays and immunoprecipitation (IP) and confocal immunofluorescence co-localization experiments. Furthermore, we demonstrated that DHT inhibited Sertad1 protein degradation in prostate cancer cell lines and that Sertad1 knockdown inhibited the proliferation of prostate cancer cells in vitro. In human PCa tumor tissues, Sertad1 expression is positively correlated with AR expression and the Gleason score. Taken together, this report is the first to show that Sertad1 is a novel AR-LBD-binding protein, and DHT-liganded AR-LBD inhibits Sertad1 degradation. Thus, Sertad1 may represent a novel therapeutic target for the treatment of AR-positive PCa.


Assuntos
Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Transativadores/metabolismo , Adulto , Animais , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Ligantes , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Proteínas Nucleares/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Domínios Proteicos , RNA Neoplásico/sangue , RNA Neoplásico/genética , Receptores Androgênicos/genética , Transativadores/genética , Fatores de Transcrição
2.
BMC Cancer ; 17(1): 795, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29179704

RESUMO

BACKGROUND: As the important suppressor of P53, iASPP is found to be overexpressed in leukemia, and functions as oncogene that inhibited apoptosis of leukemia cells. Sertad1 is identified as one of the proteins that can bind with iASPP in our previous study by two-hybrid screen. METHODS: Co-immunoprecipitation and immunofluorescence were perfomed to identified the interaction between iASPP and Sertad1 protein. Westernblot and Real-time quantitative PCR were used to determine the expression and activation of proteins. Cell proliferation assays, cell cycle and cell apoptosis were examined by flow cytometric analysis. RESULTS: iASPP combined with Sertad1 in leukemic cell lines and the interaction occurred in the cytoplasm near nuclear membrane. iASPP could interact with Sertad1 through its Cyclin-A, PHD-bromo, C terminal domain, except for S domain. Overexpression of iASPP in leukemic cells resulted in the increased cell proliferation and resistance to apoptosis induced by chemotherapy drugs. While overexpression of iASPP and Sertad1 at the same time could slow down the cell proliferation, lead the cells more vulnerable to the chemotherapy drugs, the resistance to chemotherapeutic drug in iASPPhi leukemic cells was accompanied by Puma protein expression. Excess Sertad1 protein could tether iASPP protein in the cytoplasm, further reduced the binding between iASPP and P53 in the nucleus. CONCLUSIONS: Sertad1 could antagonize iASPP function by hindering its entrance into nuclei to interact with P53 in leukemic cells when iASPP was in the stage of overproduction.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Transporte Ativo do Núcleo Celular , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Citoplasma/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Nucleares/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Transativadores/química , Fatores de Transcrição
3.
Cell Rep ; 43(2): 113752, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38341852

RESUMO

We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1ß and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
4.
Biomedicines ; 10(5)2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35625886

RESUMO

Acquired chemoresistance of tumor cells is an unwanted consequence of cancer treatment. Overcoming chemoresistance is particularly important for efficiently improving cancer therapies. Here, using multiple lines of evidence, we report the suppressive role of SERTAD1 in apoptosis/anoikis. Among various breast cancer cell lines, higher SERTAD1 expression was found in MCF7 and MDA-MB-231 in suspension than in adherent cell culture. We revealed an unexpected phenomenon that different types of cell deaths were induced in response to different doses of doxorubicin (Dox) in breast cancer cells, presumably via lysosomal membrane permeabilization. A low dose of Dox highly activated autophagy, while a high dose of the chemotherapy induced apoptosis. Inhibition of SERTAD1 promoted the sensitivity of breast cancer cells to Dox and paclitaxel, leading to a significant reduction in tumor volumes of xenograft mice. Simultaneously targeting cancer cells with Dox and autophagy inhibition successfully induced higher apoptosis/anoikis. The novel role of SERTAD1 in maintaining cellular homeostasis has also been suggested in which lysosomal contents, including LAMP1, LAMP2, CTSB, and CTSD, were reduced in SERTAD1-deficient cells.

5.
Mol Cells ; 45(4): 216-230, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35014620

RESUMO

SERTA domain-containing protein 1 (Sertad1) is upregulated in the models of DNA damage and Alzheimer's disease, contributing to neuronal death. However, the role and mechanism of Sertad1 in ischemic/hypoxic neurological injury remain unclear. In the present study, our results showed that the expression of Sertad1 was upregulated in a mouse middle cerebral artery occlusion and reperfusion model and in HT22 cells after oxygen-glucose deprivation/reoxygenation (OGD/R). Sertad1 knockdown significantly ameliorated ischemia-induced brain infarct volume, neurological deficits and neuronal apoptosis. In addition, it significantly ameliorated the OGD/R-induced inhibition of cell viability and apoptotic cell death in HT22 cells. Sertad1 knockdown significantly inhibited the ischemic/hypoxic-induced expression of p-Rb, B-Myb, and Bim in vivo and in vitro. However, Sertad1 overexpression significantly exacerbated the OGD/R-induced inhibition of cell viability and apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. In further studies, we demonstrated that Sertad1 directly binds to CDK4 and the CDK4 inhibitor ON123300 restores the effects of Sertad1 overexpression on OGD/R-induced apoptotic cell death and p-Rb, B-Myb, and Bim expression in HT22 cells. These results suggested that Sertad1 contributed to ischemic/hypoxic neurological injury by activating the CDK4/p-Rb pathway.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Apoptose , Isquemia Encefálica/genética , Glucose/metabolismo , AVC Isquêmico/genética , Camundongos , Oxigênio/metabolismo , Acidente Vascular Cerebral/genética
6.
Viruses ; 12(4)2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283651

RESUMO

E2 is the major structural glycoprotein of the classical swine fever virus (CSFV). E2 has been shown to be involved in important virus functions such as replication and virulence in swine. Using the yeast two-hybrid system, we previously identified several host proteins specifically interacting with CSFV E2. Here, we analyze the protein interaction of E2 with SERTA domain containing protein 1 (SERTAD1), a factor involved in the stimulation of the transcriptional activities of different host genes. We have confirmed that the interaction between these two proteins occurs in CSFV-infected swine cells by using a proximity ligation assay and confocal microscopy. Amino acid residues in the CSFV E2 protein that are responsible for mediating the interaction with SERTAD1 were mapped by a yeast two-hybrid approach using a randomly mutated E2 library. Using that information, a recombinant CSFV mutant (E2ΔSERTAD1v) that harbors substitutions in those residues mediating the protein-interaction with SERTAD1 was developed and used to study the role of the E2-SERTAD1 interaction in viral replication and virulence in swine. CSFV E2ΔSERTAD1v, when compared to the parental BICv, showed a clearly decreased ability to replicate in the SK6 swine cell line and a more severe replication defect in primary swine macrophage cultures. Importantly, 80% of animals infected with E2ΔSERTAD1v survived infection, remaining clinically normal during the 21-day observational period. This result would indicate that the ability of CSFV E2 to bind host SERTAD1 protein during infection plays a critical role in virus virulence.


Assuntos
Vírus da Febre Suína Clássica/fisiologia , Peste Suína Clássica/metabolismo , Peste Suína Clássica/virologia , Interações Hospedeiro-Patógeno , Fatores de Transcrição/metabolismo , Proteínas do Envelope Viral/metabolismo , Replicação Viral , Animais , Linhagem Celular , Mutação , Ligação Proteica , Suínos , Técnicas do Sistema de Duplo-Híbrido , Virulência
7.
Cancers (Basel) ; 11(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857225

RESUMO

SERTAD/TRIP-Br genes are considered as a key nuclear transcriptional player in diverse mechanisms of cell including carcinogenesis. The Oncomine™-Online Platform was used for differential expression and biological insights. Kaplan-Meier survival estimated by KM-plotter/cBioPortal/PrognoScan with 95% CI. SERTAD1 was found significantly elevated levels in most of tumor samples. Kaplan-Meier Plotter results distinctly showed the SERTAD1 over-expression significantly reduced median overall-survival (OS) of patients in liver (n = 364/Logrank-test p = 0.0015), ovarian (n = 655/Logrank-test p = 0.00011) and gastric (n = 631/Logrank-test p = 0.1866). Increased level of SERTAD1 has a significantly higher survival rate in the initial time period, but after 100 months slightly reduced OS (n = 26/Logrank-test p = 0.34) and RFS in HER2 positive breast cancer patients. In meta-analysis, cancer patients with higher SERTAD1 mRNA fold resulted worse overall survival than those with lower SERTAD1 levels. Heterogeneity was observed in the fixed effect model analysis DFS [Tau² = 0.0.073, Q (df = 4) = 15.536 (p = 0.004), I² = 74.253], DSS [Tau² = 1.015, Q (df = 2) = 33.214, (p = 0.000), I² = 93.973], RFS [Tau² = 0.492, Q (df = 7) = 71.133 (p = 0.000), I² = 90.159] (Figure 5). OS [Tau² = 0.480, Q (df = 17) = 222.344 (p = 0.000), I² = 92.354]. Lastly, SERTAD1 involved in several signaling cascades through interaction and correlation with many candidate factors as well as miRNAs. This meta-analysis demonstrates a robust evidence of an association between higher or lower SERTAD1, alteration and without alteration of SERTAD1 in cancers in terms of survival and cancer invasiveness.

8.
Cancer Lett ; 385: 271-279, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-27697611

RESUMO

Previous studies have shown that the oncogene SEI1 is highly expressed in ovarian carcinomas, and promoting genomic instability. However, the molecular mechanism of SEI1 in promoting genomic instability remains unclear. We observed SEI1 overexpression in 30 of 46 cases of ovarian cancer compared to non-tumor tissues and the overexpression of SEI1 was positively associated with the tumor FIGO stage. Our functional studies revealed that overexpression of SEI1 could induce genomic instability and increased DNA strand breaks. In contrast, SEI1 co-localized with γH2AX and phosphorylated ATM and DNAPKcs in the nucleus. Furthermore, we found that overexpression of SEI1 induced translocation of the SEI1 protein from the cytoplasm to the nucleus; ATM and DNAPKcs were associated with the cytoplasm-to-nucleus translocation of SEI1. To further prove the correlation between the DNA damage response (DDR) and SEI1, we knocked down SEI1 expression in SEI1-transfected ovarian cancer cell lines. The expression of DDR proteins was significantly downregulated, and the number of micronuclei was significantly decreased. Together, these results define a new mechanism of SEI1 in the regulation of genomic stability and in the malignant progression of ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Dano ao DNA , Reparo do DNA , Instabilidade Genômica , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Transativadores/metabolismo , Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação , Interferência de RNA , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição , Transfecção , Regulação para Cima
9.
Int J Biochem Cell Biol ; 60: 53-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25578559

RESUMO

TGF-ß plays a significant role in regulating pancreas islet function and maintaining their mass. KLF10, a TGF-ß downstream gene, belongs to a group of Krüppel-like transcription factors that bind to the promoters of target genes and produce effects that mimic TGF-ß as a tumor suppressor. Using ChIP-chip screening, SEI-1 was identified as a target gene that may be regulated by KLF10. We conducted a series of assays to verify the presence of unknown regulation events between SEI-1 and KLF10. These showed that KLF10 transcriptionally activates the SEI-1 promoter and, furthermore, induces SEI-1 protein expression in pancreatic carcinoma cells. SEI-1 is one of the key factors involved in cell cycle control through the regulation of other transcription factors such as the p21(Cip1) gene. Interestingly, it has been shown previously that p21(Cip1) is indirectly activated by KLF10. Our results first demonstrated that KLF10 acts as a transcriptional activator on SEI-1, which can then result in increased p21(Cip1) expression. Furthermore, KLF10-deficiency in mice is associated with a decrease in the pancreatic islet mass, which is similar to the effects found in SEI-1 deficient mice. The KLF10-defect was also associated with the nuclear accumulation of the p21(Cip1) in islet cells. Based on our molecular and histological findings, we conclude that KLF10 plays an important role in pancreatic ß-cells and this supports a functional link between KLF10 and various cell cycle regulators, most notably in the context of the pancreas.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Nucleares/metabolismo , Pâncreas/metabolismo , Transativadores/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Ensaio de Desvio de Mobilidade Eletroforética , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Fatores de Transcrição
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