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1.
FASEB J ; 38(18): e70068, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39302717

RESUMO

Atrial fibrosis plays a critical role in the pathogenesis of atrial fibrillation (AF). Monocyte chemotactic protein-induced protein-1 (MCPIP1), recognized as a functional ribonuclease (RNase), exacerbates cardiac remodeling and contributes to a range of cardiovascular diseases. However, the involvement of MCPIP1 in atrial fibrosis and development of AF, along with its underlying biological mechanisms, remains poorly understood. This study demonstrated that knockdown of MCPIP1 significantly reduced AF inducibility, decreased left atrial diameter, and ameliorated atrial fibrosis, coinciding with reduced FRAT1/2/Wnt/ß-catenin signaling. Furthermore, the MCPIP1-D141N mutation attenuated AF vulnerability and atrial remodeling compared to MCPIP1 overexpression in an acetylcholine and calcium chloride (ACh-CaCl2)-induced rat model of AF. Conversely, overexpression of FRAT1/2 partially reversed the cardioprotective effects of MCPIP1-D141N mutation. Using H9C2 cell lines, we observed that MCPIP1 may induce a transcriptional effect that downregulates miR-26a-5p expression, and luciferase and RNA immunoprecipitation (RIP) assays substantiated the direct interaction between miR-26a-5p and FRAT1/2. Moreover, overexpression of miR-26a-5p countered MCPIP1-induced atrial remodeling and attenuated the progression of AF. In conclusion, these findings indicate that MCPIP1 facilitates atrial remodeling and the progression of AF by exacerbating miR-26a-5p/FRAT/Wnt axis-mediated atrial fibrosis through its RNase activity in an ACh-CaCl2-induced rat model of AF.


Assuntos
Fibrilação Atrial , Remodelamento Atrial , Fibrose , Átrios do Coração , MicroRNAs , Ratos Sprague-Dawley , Ribonucleases , Via de Sinalização Wnt , Animais , Ratos , MicroRNAs/genética , MicroRNAs/metabolismo , Remodelamento Atrial/fisiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Masculino , Ribonucleases/metabolismo , Ribonucleases/genética , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Modelos Animais de Doenças , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
2.
Ann Surg Treat Res ; 103(2): 63-71, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36017142

RESUMO

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis and a lack of targeted therapy. Overexpression of FRAT1 is thought to be associated with this aggressive subtype of cancer. Here, we performed a comprehensive analysis and assessed the association between overexpression of FRAT1 and TNBC. Methods: First, using different web-based bioinformatics platforms (TIMER 2.0, UALCAN, and GEPIA 2), the expression of FRAT1 was assessed. Then, the expression of the FRAT1 protein and hormone receptors and HER2 status were assessed by immunohistochemical analysis. For samples of tumors with equivocal immunoreactivity, we performed silver in situ hybridization of the HER2 gene to determine an accurate HER2 status. Next, we used the R package and bc-GenExMiner 4.8 to analyze the relationship between FRAT1 expression and clinicopathological parameters in breast cancer patients. Finally, we determined the relationship between FRAT1 overexpression and prognosis in patients. Results: The expression of FRAT1 in breast cancer tissues is significantly higher than in normal tissue. FRAT1 expression was significantly related to worse overall survival (P < 0.05) and was correlated with these clinicopathological features: T stage, N stage, age, high histologic grade, estrogen receptor status, progesterone receptor status, Her-2 status, TNBC status, basal-like status, CK5/6 status, and Ki67 status. Conclusion: FRAT1 was overexpressed in breast cancer compared to normal tissue, and it may be involved in the progression of breast cancer malignancy. This study provides suggestive evidence of the prognostic role of FRAT1 in breast cancer and the therapeutic target for TNBC.

3.
New Phytol ; 236(2): 729-744, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35832005

RESUMO

Arabis alpina is a polycarpic perennial, in which PERPETUAL FLOWERING1 (PEP1) regulates flowering and perennial traits in a vernalization-dependent manner. Mutagenesis screens of the pep1 mutant established the role of other flowering time regulators in PEP1-parallel pathways. Here we characterized three allelic enhancers of pep1 (eop002, 085 and 091) which flower early. We mapped the causal mutations and complemented mutants with the identified gene. Using quantitative reverse transcriptase PCR and reporter lines, we determined the protein spatiotemporal expression patterns and localization within the cell. We also characterized its role in Arabidopsis thaliana using CRISPR and in A. alpina by introgressing mutant alleles into a wild-type background. These mutants carried lesions in an AAA+ ATPase of unknown function, FLOWERING REPRESSOR AAA+ ATPase 1 (AaFRAT1). AaFRAT1 was detected in the vasculature of young leaf primordia and the rib zone of flowering shoot apical meristems. At the subcellular level, AaFRAT1 was localized at the interphase between the endoplasmic reticulum and peroxisomes. Introgression lines carrying Aafrat1 alleles required less vernalization to flower and reduced number of vegetative axillary branches. By contrast, A. thaliana CRISPR lines showed weak flowering phenotypes. AaFRAT1 contributes to flowering time regulation and the perennial growth habit of A. alpina.


Assuntos
Arabidopsis , Arabis , Adenosina Trifosfatases/metabolismo , Arabidopsis/metabolismo , Arabis/genética , Arabis/metabolismo , Flores/fisiologia , Regulação da Expressão Gênica de Plantas , Meristema/metabolismo
4.
Aging (Albany NY) ; 13(14): 18527-18544, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34319909

RESUMO

Prostate cancer (PCa) is a prevalent cancer in males, with high incidence and mortality. Recent studies have shown the crucial role of long non-coding RNA (lncRNA) in PCa. Here, we aimed to explore the functional roles and inner mechanisms of lncRNA CCAT1 in PCa cells. qRT-PCR results showed that CCAT1 was upregulated in PCa tissues and cells. Functional assays demonstrated that CCAT1 knockdown suppressed cell proliferation, migration, invasion, yet promoted apoptosis, while CCAT1 promotion showed the opposite results. We also found that CCAT1 negatively regulated miR-490-3p expression and subsequently regulated FRAT1 expression. Inhibition of miR-490-3p or up-regulation of FRAT1 reversed the suppressive effects of CCAT1 knockdown on the PCa cells. In conclusion, CCAT1 regulated FRAT1 expression through miR-490-3p and then promote the PCa cells proliferation, migration, and invasion, which reveals the oncogenic function of CCAT1 in PCa progress.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Movimento Celular , Proliferação de Células , MicroRNAs/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Invasividade Neoplásica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/genética , Células Tumorais Cultivadas
5.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 185-190, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32538769

RESUMO

The current experiment was performed to investigate whether luteolin affects the proliferation and apoptosis of keloid fibroblasts by regulating the expression of FRAT1 gene. Keloid fibroblasts were treated with luteolin at different concentrations. MTT method, western blot, flow cytometry, and real-time quantitative PCR (qPCR) were used to detect cell proliferation, cyclin D1 (CyclinD1), p21, B-cell lymphoma / leukemia-2 (Bcl-2), Bcl-2 related X protein (Bax), FRAT1 protein expression, apoptosis and ARHI mRNA expression. Keloid fibroblasts were transfected with si-FRAT1, or pcDNA-FRAT1 and treated with luteolin to observe their roles in cell proliferation and apoptosis. Compared with the control group, luteolin significantly reduced the keloid fibroblast activity, CyclinD1, Bcl-2, and FRAT1 protein levels, and obviously improved the cell apoptosis rate, p21 and Bax protein expression (P<0.05). The expression of FRAT1 mRNA and protein in keloid fibroblasts was greatly increased (P<0.05). Inhibition of FRAT1 expression evidently decreased cell viability at 24 h, 48 h, and 72 h, CyclinD1, and Bcl-2 protein expression of keloid fibroblasts, while-dramatically enhanced cell apoptosis, p21, and Bax protein levels (P<0.05). FRAT1 overexpression reversed the inhibitory effect of luteolin on keloid fibroblast activity, FRAT1, CyclinD1, and Bcl-2 protein expression, and promotion of apoptosis, p21 and Bax protein expression. Luteolin can inhibit the proliferation and induce apoptosis of keloid fibroblasts by regulating the expression of FRAT1 gene.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Fibroblastos/patologia , Regulação da Expressão Gênica , Queloide/genética , Queloide/patologia , Luteolina/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas/metabolismo
6.
J Cancer ; 11(9): 2421-2430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32201513

RESUMO

Glioma stem cells (GSCs) are considered the source for development, recurrence, and poor prognosis of glioma, so treatment targeted GSCs is of great interest. The frequently rearranged in advanced T cell lymphomas-1 (FRAT1) gene is an important member of the Wnt/ß-catenin signaling transduction pathway, and aberrantly activation of Wnt signaling has been identified to contribute to the tumorigenesis, proliferation, invasion of a variety kinds of cancer stem cells. However, correlations between FRAT1 and GSCs and the specific mechanisms remain unclear. In this study, we aimed to investigate the effect of FRAT1 on GSCs proliferation, colony formation, sphere formation and tumorigenesity in vitro and in vivo and its underlying mechanism. Lentiviral transfection was used to construct GSCs with low FRAT1 expression. The expression of FRAT1 on GSCs proliferation in vitro was assessed by cell counting kit-8(CCK-8). Colony formation and sphere formation assays were conducted to assess the colony and sphere formation ability of GSCs. Then, an intracranial glioma nude mouse model was built to measure the effect of low FRAT1 expression on GSCs proliferation and tumorigenesity in vivo. Real-time PCR, Western blot, and Immunohistochemistry were processed to detect the mRNA and protein expressions of FRAT1, ß-catenin in the glioma tissue of xenograft mice to study their correlations. The functional assays verifed that low FRAT1 expression inhibited CD133+Nestin+ GSCs proliferation, colony formation, sphere formation ability in vitro. In vivo GSCs xenograft mice model showed that low FRAT1 expression suppressed the proliferation and tumorigenesity of CD133+Nestin+ GSCs and reduced ß-catenin mRNA and protein expression. Furthermore, the expression of FRAT1 and ß-catenin were positively correlated. Altogether, results indicate that FRAT1 enhances the proliferation, colony formation, sphere formation and tumorigenesity of CD133+Nestin+ glioma stem cells in vitro and in vivo as well as the expression of ß-catenin. Therefore, inhibiting proliferation of GSCs and FRAT1 may be a molecular target to GSCs in treating human glioma in the future.

7.
Thorac Cancer ; 11(2): 295-304, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31788970

RESUMO

BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most lethal type of cancer. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as crucial regulators in the development of NSCLC. The aim of our study was to explore the molecular mechanism of SNHG1 to enable better treatment for NSCLC patients. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of Small nucleolar RNA host gene 1 (SNHG1), miR-361-3p and frequently rearranged in advanced T-cell lymphomas 1 (FRAT1). The protein level of FRAT1 was measured by western blot assay. Cell proliferation was evaluated by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was assessed by flow cytometry assay. The number of migrated and invaded cells were counted by transwell assay. The relationship between miR-361-3p and SNHG1 or FRAT1 was confirmed by dual-luciferase reporter assay. RESULTS: Our results indicated that SNHG1 and FRAT1 were highly expressed in NSCLC tissues and cells. SNHG1 silencing inhibited proliferation, induced apoptosis and blocked migration and invasion of NSCLC cells. Also, FRAT1 downregulation suppressed proliferation, promoted apoptosis and hindered migration and invasion of NSCLC cells. Further, FRAT1 could recover the effects of SNHG1 silencing on proliferation, apoptosis, migration and invasion of NSCLC cells. SNHG1 sponged miR-361-3p and negatively regulated miR-361-3p expression. Meanwhile, miR-361-3p targeted FRAT1 and inversely modulated FRAT1 expression. In addition, miR-361-3p inhibition abated the effect of SNHG1 knockdown on FRAT1 expression. CONCLUSION: In conclusion, LncRNA SNHG1 promoted the proliferation, repressed apoptosis and enhanced migration and invasion of NSCLC cells by regulating FRAT1 expression via sponging miR-361-3p.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , MicroRNAs/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas/genética , Células Tumorais Cultivadas
8.
Aging (Albany NY) ; 9(3): 932-954, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28340489

RESUMO

Micro (mi)RNAs are short, noncoding RNAs and deregulation of miRNAs and their targets are implicated in tumor generation and progression in many cancers. Meningiomas are mostly benign, slow growing tumors of the central nervous system with a small percentage showing a malignant phenotype.Following in silico prediction of potential targets of miR-34a-3p, SMAD4, FRAT1, and BCL2 have been confirmed as targets by dual luciferase assays with co-expression of miR-34a-3p and reporter gene constructs containing the respective 3'UTRs. Disruption of the miR-34a-3p binding sites in the 3'UTRs resulted in loss of responsiveness to miR-34a-3p overexpression. In meningioma cells, overexpression of miR-34a-3p resulted in decreased protein levels of SMAD4, FRAT1 and BCL2, while inhibition of miR-34a-3p led to increased levels of these proteins as confirmed by Western blotting. Furthermore, deregulation of miR-34a-3p altered cell proliferation and apoptosis of meningioma cells in vitro.We show that SMAD4, FRAT1 and BCL2 are direct targets of miR-34a-3p and that deregulation of miR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro. As part of their respective signaling pathways, which are known to play a role in meningioma genesis and progression, deregulation of SMAD4, FRAT1 and BCL2 might contribute to the aberrant activation of these signaling pathways leading to increased proliferation and inhibition of apoptosis in meningiomas.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína Smad4/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular Tumoral , Simulação por Computador , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais/genética , Proteína Smad4/genética
9.
Cancer Lett ; 376(1): 178-87, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27037061

RESUMO

The Wnt/ß-catenin pathway is known to contribute to colorectal cancer (CRC) progression, although little is known about the contribution of ß-catenin on this process. We investigated the role of miR-490-3p, which was recently reported to suppress tumorigenesis through its effect on Wnt/ß-catenin signaling. We found that hypermethylation of the miR-490-3p promoter down-regulates miR-490-3p expression in CRC tissue. Gain- and loss-of-function assays in vitro and in vivo reveal that miR-490-3p suppresses cancer cell proliferation by inducing apoptosis and inhibits cell invasiveness by repressing the initiation of epithelial-to-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. The frequently rearranged in advanced T-cell lymphomas (FRAT1) protein was identified as a direct target of miR-490-3p and contributes to its tumor-suppressing effects. miR-490-3p appears to have an inhibitory effect on ß-catenin expression in nuclear fractions of CRC cells, whereas FRAT1 expression is associated with the accumulation of ß-catenin in the nucleus of cells, which could be weakened by transfection with miR-490-3p. Our findings suggest that the miR-490-3p/FRAT1/ß-catenin axis is important in CRC progression and provides new insight into the molecular mechanisms underlying CRC. They may help to confirm the pathway driving CRC aggressiveness and serve for the development of a novel miRNA-targeting anticancer therapy.


Assuntos
Neoplasias Colorretais/genética , Inativação Gênica , MicroRNAs/genética , Via de Sinalização Wnt , Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Regulação para Baixo , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Células HCT116 , Células HT29 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Tempo , Transfecção , beta Catenina/genética , beta Catenina/metabolismo
10.
Oncol Lett ; 12(6): 4761-4766, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28101222

RESUMO

Colorectal cancer is one of the most common gastric malignancies worldwide. However, the underlying mechanism of colon cancer development and valuable indicators of the disease remain unclear. In this study, the expression of frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) in colon cancer was investigated and the association between FRAT1 expression and biological properties of tumors was analyzed. A total of 147 colon cancer tissue samples and adjacent normal tissues were collected between January 2013 and June 2014. The FRAT1 gene and protein expression levels were analyzed in tissues with different TNM and pathological stages. Small hairpin RNAs (shRNAs) containing the human FRAT1 gene were constructed and transfected into colon cancer HT-29 cells. The proliferation and migration of the cells was also analyzed in relation to a reduction in FRAT1 expression. In colon cancer tissues, the expression of FRAT1 was significantly higher when compared with adjacent tissues. In addition, FRAT1 expression was found to positively correlate with the degree of tumor malignancy, and this difference was determined to be statistically significant (P<0.05). Following shRNA transfection in HT-29 cells to decrease the expression of FRAT1, the proliferation and migration of the HT-29 cells decreased (due to conversion of the shRNA into small interfering RNA). These results indicate that in colon cancer, FRAT1 may present a novel tool for analyzing the tumor progression and may be a novel therapeutic target for the treatment of colon cancer.

11.
Tumour Biol ; 36(12): 9961-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26178481

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) and ATP-binding cassette subfamily G member 2 (ABCG2) expression in PDAC. FRAT1 and ABCG2 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic tissues, and 13 normal pancreatic tissues was measured by immunohistochemistry. FRAT1 and ABCG2 protein was overexpressed in PDAC tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P < 0.01). The percentage of cases with positive FRAT1 and ABCG2 overexpression was significantly higher in PDAC patients with poor differentiation, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with well-differentiated tumor, no lymph node metastasis and invasion, and TNM stage I/II disease (P < 0.05 or P < 0.01). In pancreatic tissues with benign lesions, tissues with positive FRAT1 and ABCG2 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive FRAT1 and ABCG2 expression survived significantly shorter than patients with negative FRAT1 and ABCG2 expression (P < 0.05 or P < 0.001). Cox multivariate analysis revealed that positive FRAT1 and ABCG2 expression was an independent poor prognosis factor in PDAC patients. FRAT1 and ABCG2 overexpression is associated with carcinogenesis, progression, and poor prognosis in patients with PDAC.


Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Adenocarcinoma/genética , Biomarcadores Tumorais/biossíntese , Carcinoma Ductal Pancreático/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas/genética
12.
J Cell Sci ; 127(Pt 14): 3116-30, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24829151

RESUMO

N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor ß (TGF-ß)-induced epithelial-to-mesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and ß-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of ß-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated ß-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting ß-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3ß-binding protein FRAT1, which prevents the association of GSK3ß with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of ß-catenin. Additionally, NDRG1 is shown to modulate the WNT-ß-catenin pathway by inhibiting the nuclear translocation of ß-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for ß-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of ß-catenin phosphorylation and distribution.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , beta Catenina/metabolismo , Quinases Ativadas por p21/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Inativação Gênica , Células HCT116 , Células HT29 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosforilação , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Transfecção , Quinases Ativadas por p21/genética
13.
Artigo em Inglês | MEDLINE | ID: mdl-24013142

RESUMO

The herbicide linuron (LIN) is an endocrine disruptor with an anti-androgenic mode of action. The objectives of this study were to (1) improve knowledge of androgen and anti-androgen signaling in the teleostean ovary and to (2) assess the ability of gene networks and machine learning to classify LIN as an anti-androgen using transcriptomic data. Ovarian explants from vitellogenic fathead minnows (FHMs) were exposed to three concentrations of either 5α-dihydrotestosterone (DHT), flutamide (FLUT), or LIN for 12h. Ovaries exposed to DHT showed a significant increase in 17ß-estradiol (E2) production while FLUT and LIN had no effect on E2. To improve understanding of androgen receptor signaling in the ovary, a reciprocal gene expression network was constructed for DHT and FLUT using pathway analysis and these data suggested that steroid metabolism, translation, and DNA replication are processes regulated through AR signaling in the ovary. Sub-network enrichment analysis revealed that FLUT and LIN shared more regulated gene networks in common compared to DHT. Using transcriptomic datasets from different fish species, machine learning algorithms classified LIN successfully with other anti-androgens. This study advances knowledge regarding molecular signaling cascades in the ovary that are responsive to androgens and anti-androgens and provides proof of concept that gene network analysis and machine learning can classify priority chemicals using experimental transcriptomic data collected from different fish species.


Assuntos
Antagonistas de Androgênios/farmacologia , Disruptores Endócrinos/farmacologia , Redes Reguladoras de Genes/efeitos dos fármacos , Linurona/farmacologia , Receptores Androgênicos/efeitos dos fármacos , Poluentes Químicos da Água/farmacologia , Animais , Inteligência Artificial , Cyprinidae , Di-Hidrotestosterona/farmacologia , Estradiol/biossíntese , Feminino , Flutamida/farmacologia , Perfilação da Expressão Gênica , Ovário/efeitos dos fármacos , Transdução de Sinais , Máquina de Vetores de Suporte
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