RESUMO
ANKHD1 (ankyrin repeat and KH domain containing 1) is a large protein characterized by the presence of multiple ankyrin repeats and a K-homology domain. Ankyrin repeat domains consist of widely existing protein motifs in nature, they mediate protein-protein interactions and regulate fundamental biological processes, while the KH domain binds to RNA or ssDNA and is associated with transcriptional and translational regulation. In recent years, studies containing relevant information on ANKHD1 in cancer biology and its clinical relevance, as well as the increasing complexity of signaling networks in which this protein acts, have been reported. Among the signaling pathways of interest in oncology regulated by ANKHD1 are Hippo signaling, JAK/STAT, and STMN1. The scope of the present review is to survey the current knowledge and highlight future perspectives for ANKHD1 in the malignant phenotype of cancer cells, exploring biological, functional, and clinical reports of this protein in cancer. [BMB Reports 2020; 53(8): 413-418].
Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Motivos de Aminoácidos , Sítios de Ligação/genética , Fenômenos Biológicos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Janus Quinase 1/metabolismo , Domínios Proteicos/fisiologia , RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Estatmina/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
Posttranscriptional regulation plays a fundamental role in the biology of embryonic stem cells (ESCs). Many studies have demonstrated that multiple mRNAs are coregulated by one or more RNA-binding proteins (RBPs) that orchestrate mRNA expression. A family of RBPs, which is known as the Pumilio-FBF (PUF) family, is highly conserved among different species and has been associated with the undifferentiated and differentiated states of different cell lines. In humans, two homologs of the PUF family have been found: Pumilio 1 (PUM1) and Pumilio 2 (PUM2). To understand the role of these proteins in human ESCs (hESCs), we first assessed the influence of the silencing of PUM1 and PUM2 on pluripotency genes and found that the knockdown of Pumilio genes significantly decreased the OCT4 and NANOG mRNA levels and reduced the amount of nuclear OCT4, which suggests that Pumilio proteins play a role in the maintenance of pluripotency in hESCs. Furthermore, we observed that PUM1-and-PUM2-silenced hESCs exhibited improved efficiency of in vitro cardiomyogenic differentiation. Through an in silico analysis, we identified mRNA targets of PUM1 and PUM2 that are expressed at the early stages of cardiomyogenesis, and further investigation will determine whether these target mRNAs are active and involved in the progression of cardiomyogenesis. Our findings contribute to the understanding of the role of Pumilio proteins in hESC maintenance and differentiation.
Assuntos
Células-Tronco Embrionárias Humanas/metabolismo , Proteínas de Ligação a RNA/fisiologia , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Embrionárias Humanas/citologia , Humanos , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Mensageiro/metabolismoRESUMO
Musashi comprises an evolutionarily conserved family of RNA-binding proteins (RBP) that regulate cell fate decisions during embryonic development and play key roles in the maintenance of self-renewal and differentiation of stem cells and adult tissues. More recently, several studies have shown that any dysregulation of MSI1 and MSI2 can lead to cellular dysfunctions promoting tissue instability and tumorigenesis. Moreover, several reports have characterized many molecular interactions between members of the Musashi family with ligands and receptors of the signaling pathways responsible for controlling normal embryonic development: Notch, Transforming Growth Factor Beta (TGF-ß), Wingless (Wnt) and Hedgehog Signaling (Hh); all of which, when altered, are strongly associated with cancer onset and progression, especially in pediatric tumors. In this context, the present review aims to compile possible cross-talks between Musashi proteins and members of the above cited molecular pathways for which dysregulation plays important roles during carcinogenesis and may be modulated by these RBP.
Assuntos
Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/fisiologia , Proteínas de Ligação a RNA/fisiologia , Transdução de Sinais , Animais , Carcinogênese , Diferenciação Celular , Desenvolvimento Embrionário , HumanosRESUMO
Cellular mRNAs cycle between translating and non-translating pools, polysomes compose the translating pool, while RNA granules contain translationally-silenced mRNAs, where the RNAs are either stored in stress granules, or accumulate in processing bodies (PBs) or GW-bodies, which have an important role in RNA degradation. Viruses have developed measures to prevent the deleterious effects of these structures during their replication. Rotavirus, the most common agent of viral gastroenteritis, is capable of establishing a successful infection by counteracting several of the antiviral responses of its host. Here, we describe that in rotavirus-infected cells the distribution of several RNA binding proteins is changed causing the disaggregation of PBs, the relocalization of GW-body proteins, and the cytoplasmic accumulation of HuR, a predominantly nuclear protein. We show that this redistribution of proteins is more likely caused by the accumulation of viral RNA in the cytoplasm of infected-cells, where it might be acting as an RBP sponge.
Assuntos
Transporte Proteico/fisiologia , RNA Viral/fisiologia , Proteínas de Ligação a RNA/fisiologia , Rotavirus/genética , Animais , Anticorpos Antivirais , Linhagem Celular , Regulação da Expressão Gênica , Macaca mulatta , RNA Mensageiro/química , RNA Mensageiro/fisiologia , Proteínas de Ligação a RNA/química , Rotavirus/fisiologiaRESUMO
BACKGROUND: Cellular nucleic acid binding protein (CNBP) is a small and highly conserved protein with nucleic acid chaperone activity that binds single-stranded nucleic acids. Data collected so far suggests that CNBP is required for proper craniofacial development. Despite the advances achieved in the last decade, the identity of the molecular targets of CNBP responsible for its role in rostral head development remains elusive. METHODS: In this work we used the CNBP single-stranded DNA-consensus binding sequence to find out putative CNBP target genes present in the human, mouse, chicken, Xenopus and zebrafish genomes. RESULTS: Most of the identified genes are associated with embryonic developmental processes, being three of them (cdk14, ptk7 and tcf7l2) members of the Wnt signaling pathway. This finding, along with previous one showing that CNBP down-regulates the transcription of Wnt5, aimed our work to address the role of CNBP on the WNT signaling players and pathway regulation. Experiments carried out in zebrafish developing embryos revealed that craniofacial morphology was more adversely affected as CNBP abundance decreased. Furthermore, we observed that CNBP up-regulated in a dose-dependent fashion the transcription of cdk14, ptk7 and tcf7l2, which in turn was reflected in c-myc, ccnd1 and axin2 expression. CONCLUSIONS: RESULTS reveal a role of CNBP in transcriptional control of components of the Wnt signaling pathway, which might explain its requirement for proper craniofacial development.
Assuntos
Proteínas de Ligação a RNA/fisiologia , Via de Sinalização Wnt/genética , Proteínas de Peixe-Zebra/fisiologia , Animais , Desenvolvimento Ósseo/genética , Galinhas , Embrião não Mamífero , Face/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Receptores Proteína Tirosina Quinases/genética , Crânio/embriologia , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Xenopus , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genéticaRESUMO
ANKHD1 is a multiple ankyrin repeat containing protein, recently identified as a novel member of the Hippo signaling pathway. The present study aimed to investigate the role of ANKHD1 in DU145 and LNCaP prostate cancer cells. ANKHD1 and YAP1 were found to be highly expressed in prostate cancer cells, and ANKHD1 silencing decreased cell growth, delayed cell cycle progression at the S phase, and reduced tumor xenograft growth. Moreover, ANKHD1 knockdown downregulated YAP1 expression and activation, and reduced the expression of CCNA2, a YAP1 target gene. These findings indicate that ANKHD1 is a positive regulator of YAP1 and promotes cell growth and cell cycle progression through Cyclin A upregulation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Fosfoproteínas/genética , Neoplasias da Próstata/genética , Proteínas de Ligação a RNA/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Ciclina A/genética , Ciclina A/metabolismo , Células HeLa , Via de Sinalização Hippo , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição , Ativação Transcricional , Proteínas de Sinalização YAPRESUMO
Human Interleukin-3 (IL-3) is a lymphokine member of a class of transiently expressed mRNAs harboring Adenosine/Uridine-Rich Elements (ARE) in their 3' untranslated regions (3'-UTRs). The regulatory effects of AREs are often mediated by specific ARE-binding proteins (ARE-BPs). In this report, we show that the human IL-3 3'-UTR plays a post-transcriptional regulation role in two human transformed cell lines. More specifically, we demonstrate that the hIL-3 3'-UTR represses the translation of a luciferase reporter both in HeLa and Jurkat T-cells. These results also revealed that the hIL-3 3'-UTR-mediated translational repression is exerted by an 83 nt region comprised mainly by AREs and some non-ARE sequences. Moreover, electrophoretic mobility shift assays (EMSAs) and UV-crosslinking analysis show that this hIL-3 ARE-rich region recruits five specific protein complexes, including the ARE-BPs HuR and TIA-1. HuR binding to this ARE-rich region appears to be spatially modulated during T-cell activation. Together, these results suggest that HuR recognizes the ARE-rich region and plays a role in the IL-3 3'-UTR-mediated post-transcriptional control in T-cells.
Assuntos
Regiões 3' não Traduzidas , Proteínas ELAV/fisiologia , Interleucina-3/genética , Interleucina-3/metabolismo , Proteínas de Ligação a RNA/fisiologia , Proteína Semelhante a ELAV 1 , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Células Jurkat , Ativação Linfocitária , Proteínas de Ligação a Poli(A)/fisiologia , Antígeno-1 Intracelular de Células T , Transformação GenéticaRESUMO
To characterise the trypanosomatid-exclusive RNA-binding protein TcRBP19, we analysed the phenotypic changes caused by its overexpression. Although no evident changes were observed when TcRBP19 was ectopically expressed in epimastigotes, the metacyclogenesis process was affected. Notably, TcRBP19 overexpression also led to a decrease in the number of infected mammalian cells. These findings suggest that TcRBP19 may be involved in the life cycle progression of the Trypanosoma cruzi parasite.
Assuntos
Animais , Proteínas de Protozoários/fisiologia , Proteínas de Ligação a RNA/genética , Trypanosoma cruzi/genética , Regulação da Expressão Gênica , Estágios do Ciclo de Vida , Processamento Pós-Transcricional do RNA/genética , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/fisiologia , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismoRESUMO
The formation of the nervous systems requires processes that coordinate proliferation, differentiation and migration of neuronal cells, which extend axons, generate dendritic branching and establish synaptic connections during development. The structural organization and dynamic remodeling of the cytoskeleton and its association to the secretory pathway are critical determinants of cell morphogenesis and migration. Marlin-1 (Jakmip1) is a microtubule-associated protein predominantly expressed in neurons and lymphoid cells. Marlin-1 participates in polarized secretion in lymphocytes, but its functional association with the neuronal cytoskeleton and its contribution to brain development have not been explored. Combining in vitro and in vivo approaches we show that Marlin-1 contributes to the establishment of neuronal morphology. Marlin-1 associates to the cytoskeleton in neurites, is required for the maintenance of an intact Golgi apparatus and its depletion produces the down-regulation of kinesin-1, a plus-end directed molecular motor with a central function in morphogenesis and migration. RNA interference of Marlin-1 in vivo results in abnormal migration of newborn pyramidal neurons during the formation of the cortex. Our results support the involvement of Marlin-1 in the acquisition of the complex architecture and migration of pyramidal neurons, two fundamental processes for the laminar layering of the cortex.
Assuntos
Movimento Celular , Neurogênese , Células Piramidais/embriologia , Proteínas de Ligação a RNA/fisiologia , Animais , Movimento Celular/genética , Citoesqueleto/metabolismo , Feminino , Complexo de Golgi/metabolismo , Cinesinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neurogênese/genética , Células Piramidais/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Ratos , Ratos Sprague-DawleyRESUMO
To characterise the trypanosomatid-exclusive RNA-binding protein TcRBP19, we analysed the phenotypic changes caused by its overexpression. Although no evident changes were observed when TcRBP19 was ectopically expressed in epimastigotes, the metacyclogenesis process was affected. Notably, TcRBP19 overexpression also led to a decrease in the number of infected mammalian cells. These findings suggest that TcRBP19 may be involved in the life cycle progression of the Trypanosoma cruzi parasite.