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1.
J Biochem Mol Toxicol ; 38(4): e23685, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38495002

RESUMO

Neurodegeneration is linked to the progressive loss of neural function and is associated with several diseases. Hypoxia is a hallmark in many of these diseases, and several therapies have been developed to treat this disease, including gene expression therapies that should be tightly controlled to avoid side effects. Cells experiencing hypoxia undergo a series of physiological responses that are induced by the activation of various transcription factors. Modulation of microRNA (miRNA) expression to alter transcriptional regulation has been demonstrated to be beneficial in treating multiple diseases, and in this study, we therefore explored potential miRNA candidates that could influence hypoxia-induced nerve cell death. Our data suggest that in mouse neuroblasts Neuro-2a cells with hypoxia/reoxygenation (H/R), miR-337-3p is downregulated to increase the expression of Potassium channel tetramerization domain containing 11 (KCTD11) and subsequently promote apoptosis. Here, we demonstrate for the first time that KCTD11 plays a role in the cellular response to hypoxia, and we also provide a possible regulatory mechanism by identifying the axis of miR-337-3p/KCTD11 as a promising candidate modulator of nerve cell survival after H/R exposure.


Assuntos
MicroRNAs , Neuroblastoma , Animais , Camundongos , Regulação para Baixo , Regulação da Expressão Gênica , Hipóxia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neuroblastoma/genética
2.
J Cell Mol Med ; 25(19): 9411-9426, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34453479

RESUMO

KCTD11 has been reported to be a potential tumour suppressor in several tumour types. However, the expression of KCTD11 and its role has not been reported in human non-small cell lung cancer (NSCLC). Whether its potential molecular mechanism is related to its BTB domain is also unknown. The expression of KCTD11 in 139 NSCLC tissue samples was detected by immunohistochemistry, and its correlation with clinicopathological factors was analysed. The effect of KCTD11 on the biological behaviour of lung cancer cells was verified in vitro and in vivo. Its effect on the epithelial-mesenchymal transition(EMT)process and the Wnt/ß-catenin and Hippo/YAP pathways were observed by Western blot, dual-luciferase assay, RT-qPCR, immunofluorescence and immunoprecipitation. KCTD11 is under-expressed in lung cancer tissues and cells and was negatively correlated with the degree of differentiation, tumour-node-metastasis (TNM) stage and lymph node metastasis. Low KCTD11 expression was associated with poor prognosis. KCTD11 overexpression inhibited the proliferation and migration of lung cancer cells. Further studies indicated that KCTD11 inhibited the Wnt pathway, activated the Hippo pathway and inhibited EMT processes by inhibiting the nuclear translocation of ß-catenin and YAP. KCTD11 lost its stimulatory effect on the Hippo pathway after knock down of ß-catenin. These findings confirm that KCTD11 inhibits ß-catenin and YAP nuclear translocation as well as the malignant phenotype of lung cancer cells by interacting with ß-catenin. This provides an important experimental basis for the interaction between KCTD11, ß-catenin and YAP, further revealing the link between the Wnt and Hippo pathways.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Via de Sinalização Hippo , Neoplasias Pulmonares/metabolismo , Transferases/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adulto , Idoso , Animais , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Expressão Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Fatores de Transcrição/metabolismo , Transferases/química , Transferases/genética
3.
Curr Genet ; 65(3): 701-709, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30701278

RESUMO

A critical function of human, yeast, and bacterial cells is the ability to sense and respond to available nutrients such as glucose and amino acids. Cells must also detect declining nutrient levels to adequately prepare for starvation conditions by inhibiting cell growth and activating autophagy. The evolutionarily conserved protein complex TORC1 regulates these cellular responses to nutrients, and in particular to amino acid availability. Recently, we found that yeast Whi2 (Saccharomyces cerevisiae) and a human counterpart, KCTD11, that shares a conserved BTB structural domain, are required to suppress TORC1 activity under low amino acid conditions. Using yeast, the mechanisms were more readily dissected. Unexpectedly, Whi2 suppresses TORC1 activity independently of the well-known SEACIT-GTR pathway, analogous to the GATOR1-RAG pathway in mammals. Instead, Whi2 requires the plasma membrane-associated phosphatases Psr1 and Psr2, which were known to bind Whi2, although their role was unknown. Yeast WHI2 was previously reported to be involved in regulating several fundamental cellular processes including cell cycle arrest, general stress responses, the Ras-cAMP-PKA pathway, autophagy, and mitophagy, and to be frequently mutated in the yeast knockout collections and in genome evolution studies. Most of these observations are likely explained by the ability of Whi2 to inhibit TORC1. Thus, understanding the function of yeast Whi2 will provide deeper insights into the disease-related KCTD family proteins and the pathogenesis of plant and human fungal infections.


Assuntos
Aminoácidos/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Humanos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
4.
Neoplasia ; 43: 100926, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37597490

RESUMO

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.


Assuntos
Neoplasias Cerebelares , Proteínas Hedgehog , Masculino , Humanos , Proteínas Hedgehog/genética , Proteína GLI1 em Dedos de Zinco/genética , Proliferação de Células , Bases de Dados Factuais , Proteínas Correpressoras
5.
CNS Neurosci Ther ; 25(7): 887-902, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31197948

RESUMO

The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well-characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders (KCTD3), neurodevelopmental disease (KCTD7), bipolar disorder (KCTD12), autism and schizophrenia (KCTD13), movement disorders (KCTD17), cancer (KCTD11), and obesity (KCTD15). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD-related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy-lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure-based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.


Assuntos
Transtornos do Neurodesenvolvimento/metabolismo , Proteínas/metabolismo , Animais , Humanos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/genética , Proteínas/genética
6.
Reprod Biol ; 19(2): 173-178, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31151753

RESUMO

The tumor suppressor gene KCTD11 plays a critical role in cell proliferation, differentiation and invasion. The current study investigated the regulation and the spatiotemporal expression pattern of Kctd11 in the rat ovary during the periovulatory period. Ovaries, granulosa cells, or theca-interstitial cells were collected at various times after hCG administration using an established gonadotropin-primed immature rat model that induces follicular development and ovulation. Real-time quantitative PCR analysis revealed that mRNA for Kctd11 was significantly induced both in theca-intersititial and granulosa cells after hCG treatment although their temporal expression patterns differed. In situ hybridization analysis demonstrated that Kctd11 mRNA expression was induced in theca-intersititial cells at 6 h after hCG, and the expression remained elevated until 12 h after hCG. Kctd11 mRNA was stimulated in granulosa cells at 6 h and reached the highest expression at 12 h. There was negligible Kctd11 mRNA signal observed in newly forming corpora lutea. In addition, the data indicate that both the protein kinase A and the protein kinase C pathway regulate the expression of Kctd11 mRNA in granulosa cells. Either forskolin or phorbol 12 myristate 13-acetate can mimic hCG induction of Kctd11 expression. Furthermore, the stimulation of Kctd11 by hCG requires new protein synthesis. Inhibition of progesterone action and the EGF pathway blocked Kctd11 mRNA expression, whereas inhibition of prostaglandin synthesis had no effect. Our finding suggest that the induction of the Kctd11 may be important for theca and granulosa cell differentiation into luteal cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Ovário/metabolismo , Ovulação/fisiologia , Transferases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Gonadotropina Coriônica/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Células Tecais/fisiologia , Transferases/genética , Proteínas Supressoras de Tumor/genética
7.
Oncotarget ; 8(23): 37717-37729, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28465479

RESUMO

A lack of effective prognostic biomarkers and molecular targets is a serious problem in hepatocellular carcinoma. KCTD11, reported as a tumor suppressor, are still not well understood. In this study, KCTD11 was found low-expressed in HCC tissues and cell lines. The HCC patients with low expression of KCTD11 suggested shorter overall survival. We found KCTD11 inhibiting cell proliferation in vitro and tumor growth in vivo, by activating p21 and repressing cycle related proteins. KCTD11 also inhibited cell adhesion by decreasing CTGF and CLDN1. We found CTGF binding COL3A1 in HCCLM3, which might lead to reduction of COL3A1 expression. KCTD11 also inhibited cell migration and invasion in HCC, by repressing MMPs and EMT. We found the tumor suppression function of KCTD11 was at least partly through activating Hippo pathway in HCC. Base on the enhanced Hippo pathway, KCTD11 could activate p21 by stabilizing p53 or promoting the MST1/ GSK3ß/p21 signaling in HCC. Overall, these results suggest that KCTD11 works as a tumor suppressor and owns prognostic and therapeutic potentials in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Canais de Potássio/genética , Proteínas Serina-Treonina Quinases/genética , Apoptose , Carcinoma Hepatocelular/patologia , Adesão Celular , Proteínas de Ciclo Celular , Proliferação de Células , Via de Sinalização Hippo , Humanos , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Canais de Potássio/metabolismo , Prognóstico , Transdução de Sinais , Transfecção , Transferases
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