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1.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361060

RESUMO

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.


Assuntos
Sistema Nervoso Central/patologia , Fibrose/patologia , Miocárdio/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Feminino , Fibrose/metabolismo , Proteínas HMGA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Neurônios/metabolismo , Fenótipo , Fosforilação
2.
Nature ; 595(7866): 278-282, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34098567

RESUMO

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1-3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.


Assuntos
Anticorpos Neutralizantes/imunologia , Camelídeos Americanos/imunologia , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/isolamento & purificação , Sistemas CRISPR-Cas , Camelídeos Americanos/genética , Feminino , Edição de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutação , Testes de Neutralização , SARS-CoV-2/química , SARS-CoV-2/genética , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/isolamento & purificação , Hipermutação Somática de Imunoglobulina/genética
3.
Nature ; 590(7845): 338-343, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33442057

RESUMO

RAG endonuclease initiates Igh V(D)J recombination in progenitor B cells by binding a JH-recombination signal sequence (RSS) within a recombination centre (RC) and then linearly scanning upstream chromatin, presented by loop extrusion mediated by cohesin, for convergent D-RSSs1,2. The utilization of convergently oriented RSSs and cryptic RSSs is intrinsic to long-range RAG scanning3. Scanning of RAG from the DJH-RC-RSS to upstream convergent VH-RSSs is impeded by D-proximal CTCF-binding elements (CBEs)2-5. Primary progenitor B cells undergo a mechanistically undefined contraction of the VH locus that is proposed to provide distal VHs access to the DJH-RC6-9. Here we report that an inversion of the entire 2.4-Mb VH locus in mouse primary progenitor B cells abrogates rearrangement of both VH-RSSs and normally convergent cryptic RSSs, even though locus contraction still occurs. In addition, this inversion activated both the utilization of cryptic VH-RSSs that are normally in opposite orientation and RAG scanning beyond the VH locus through several convergent CBE domains to the telomere. Together, these findings imply that broad deregulation of CBE impediments in primary progenitor B cells promotes RAG scanning of the VH locus mediated by loop extrusion. We further found that the expression of wings apart-like protein homologue (WAPL)10, a cohesin-unloading factor, was low in primary progenitor B cells compared with v-Abl-transformed progenitor B cell lines that lacked contraction and RAG scanning of the VH locus. Correspondingly, depletion of WAPL in v-Abl-transformed lines activated both processes, further implicating loop extrusion in the locus contraction mechanism.


Assuntos
Linfócitos B/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Proteínas de Homeodomínio/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Conformação de Ácido Nucleico , Animais , Linfócitos B/citologia , Linfócitos B/enzimologia , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Endonucleases/deficiência , Endonucleases/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas/genética , Proteínas/metabolismo , Recombinação V(D)J/genética
4.
Mol Med Rep ; 21(3): 1501-1508, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016459

RESUMO

Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide. It is also the second most common cause of cancer­associated mortality; it accounted for about 9.2% of all cancer deaths in 2018, most of which were due to resistance to therapy. The main treatment for CRC is surgery, generally associated with chemotherapy, radiation therapy and combination therapy. However, while chemo­radiotherapy kills differentiated cancer cells, mesenchymal stem­like cells are resistant to this treatment, and this can give rise to therapy­resistant tumors. Our previous study isolated T88 primary colon cancer cells from a patient with sporadic colon cancer. These cells exhibited mesenchymal and epithelial features, high levels of epithelial­to­mesenchymal transition transcription factors, and stemness markers. In addition, it was revealed that lithium chloride (LiCl), a specific glycogen synthase kinase (GSK)­3ß inhibitor, induced both the mesenchymal­to­epithelial transition and differentiation, and also reduced cell migration, stemness features and cell plasticity in these primary colon cancer cells. The aim of the present study was to investigate the effect of LiCl treatment on the viability of primary colon cancer cells exposed to 7 Gy delivered by high­energy photon beams, which corresponds to 6 megavolts of energy. To achieve this aim, the viability of irradiated T88 cells was compared with that of irradiated T88 cells pre­treated with LiCl. As expected, it was observed that LiCl sensitized primary colon cancer cells to high­energy photon irradiation treatment. Notably, the decrease in cell viability was greater with combined therapy than with irradiation alone. To explore the molecular basis of this response, the effect of LiCl on the expression of Bax, p53 and Survivin, which are proteins involved in the apoptotic mechanism and in death escape, was analyzed. The present study revealed that LiCl upregulated the expression of pro­apoptotic proteins and downregulated the expression of proteins involved in survival. These effects were enhanced by high­energy photon irradiation, suggesting that LiCl could be used to sensitize colon cancer cells to radiation therapy.


Assuntos
Cloreto de Lítio/farmacologia , Fótons , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/radioterapia , Humanos , Radioterapia de Alta Energia/métodos , Transdução de Sinais/efeitos dos fármacos
5.
Cell Death Dis ; 10(10): 747, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582725

RESUMO

The serine-threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.


Assuntos
Proteína HMGA1a/genética , Proteínas Serina-Treonina Quinases/genética , Doenças Respiratórias/genética , Glândula Tireoide/anormalidades , Animais , Animais Recém-Nascidos , Desenvolvimento Embrionário , Deleção de Genes , Regulação da Expressão Gênica , Proteína HMGA1a/metabolismo , Células HeLa , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Associadas a Surfactantes Pulmonares , Doenças Respiratórias/patologia , Glândula Tireoide/embriologia , Glândula Tireoide/patologia
6.
Biochim Biophys Acta Mol Cell Res ; 1866(12): 118529, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31412274

RESUMO

Many cell stressors block protein translation, inducing formation of cytoplasmic aggregates. These aggregates, named stress granules (SGs), are composed by translationally stalled ribonucleoproteins and their assembly strongly contributes to cell survival. Composition and dynamics of SGs are thus important starting points for identifying critical factors of the stress response. In the present study we link components of the H/ACA snoRNP complexes, highly concentrated in the nucleoli and the Cajal bodies, to SG composition. H/ACA snoRNPs are composed by a core of four highly conserved proteins -dyskerin, Nhp2, Nop10 and Gar1- and are involved in several fundamental processes, including ribosome biogenesis, RNA pseudouridylation, stabilization of small nucleolar RNAs and telomere maintenance. By taking advantage of cells overexpressing a dyskerin splice variant undergoing a dynamic intracellular trafficking, we were able to show that H/ACA snoRNP components can participate in SG formation, this way contributing to the stress response and perhaps transducing signals from the nucleus to the cytoplasm. Collectively, our results show for the first time that H/ACA snoRNP proteins can have additional non-nuclear functions, either independently or interacting with each other, thus further strengthening the close relationship linking nucleolus to SG composition.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Grânulos Citoplasmáticos/metabolismo , Proteínas Nucleares/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/isolamento & purificação , Células HeLa , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/isolamento & purificação , Células Tumorais Cultivadas
7.
Cell Physiol Biochem ; 47(5): 1951-1976, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29969760

RESUMO

A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.


Assuntos
Envelhecimento/metabolismo , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Transdução de Sinais , Envelhecimento/genética , Envelhecimento/patologia , Animais , Humanos , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
8.
Microrna ; 7(3): 178-186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29793420

RESUMO

The Homeodomain-Interacting Protein Kinases (HIPKs) HIPK1, HIPK2 and HIPK3 are Ser/Thr kinases which interact with homeobox proteins and other transcription factors, acting as transcriptional coactivators or corepressors. HIPKs contribute to regulate several biological processes, such as signal transduction, apoptosis, embryonic development, DNA-damage response, and cellular proliferation, in response to various extracellular stimuli. Recently it has emerged that, in addition to their role in cancer, fibrosis and diabetes, HIPKs may also be involved in other human diseases, including Amyotrophic Lateral Sclerosis (ALS), Rett syndrome, cerebellar diseases, and retinal vascular dysfunction. METHODS: Here, we update our previous paper concerning the regulation of HIPK proteins expression by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and diseases which are affected by the interplay between HIPKs and miRNAs. CONCLUSION: Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction, astrogliosis and cancer.


Assuntos
Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/genética , Neoplasias/genética , Proteínas Serina-Treonina Quinases/metabolismo , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
9.
Cell Death Differ ; 24(11): 1948-1962, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28777374

RESUMO

High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.


Assuntos
Autofagia , Proteína HMGA1a/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proliferação de Células , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Inativação Gênica , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transcrição Genética
10.
Int J Mol Sci ; 17(9)2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27649143

RESUMO

Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.


Assuntos
Antioxidantes/farmacocinética , Quinase 2 de Adesão Focal/genética , Próstata/efeitos dos fármacos , Próstata/metabolismo , Estilbenos/farmacologia , Autofagia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Quinase 2 de Adesão Focal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mutação , Estresse Oxidativo/efeitos dos fármacos , Próstata/citologia , Resveratrol
11.
Virology ; 496: 1-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27236740

RESUMO

Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC.


Assuntos
Carcinoma de Células Escamosas/etiologia , Regulação Viral da Expressão Gênica , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/fisiologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Ativação Transcricional , Animais , Proteínas de Transporte , Gatos , Linhagem Celular , Camundongos , Infecções por Papillomavirus/veterinária , Ligação Proteica , RNA Mensageiro/genética , Transdução de Sinais
12.
Cell Cycle ; 15(6): 812-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26889953

RESUMO

The High Mobility Group A1 proteins (HMGA1) are nonhistone chromatinic proteins with a critical role in development and cancer. We have recently reported that HMGA1 proteins are able to increase the expression of spindle assembly checkpoint (SAC) genes, thus impairing SAC function and causing chromosomal instability in cancer cells. Moreover, we found a significant correlation between HMGA1 and SAC genes expression in human colon carcinomas. Here, we report that mouse embryonic fibroblasts null for the Hmga1 gene show downregulation of Bub1, Bub1b, Mad2l1 and Ttk SAC genes, and present several features of chromosomal instability, such as nuclear abnormalities, binucleation, micronuclei and karyotypic alterations. Interestingky, also MEFs carrying only one impaired Hmga1 allele present karyotypic alterations. These results indicate that HMGA1 proteins regulate SAC genes expression and, thereby, genomic stability also in embryonic cells.


Assuntos
Instabilidade Cromossômica , Fibroblastos/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular , Proteína HMGA1a/genética , Pontos de Checagem da Fase M do Ciclo Celular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/genética , Núcleo Celular/patologia , Embrião de Mamíferos , Fibroblastos/patologia , Regulação da Expressão Gênica , Teste de Complementação Genética , Proteína HMGA1a/deficiência , Cariótipo , Camundongos , Camundongos Knockout , Micronúcleos com Defeito Cromossômico , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
13.
Microrna ; 4(3): 148-57, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26428079

RESUMO

INTRODUCTION: The homeodomain-interacting protein kinase (HIPK) family consists of four evolutionarily conserved and highly related nuclear serine/threonine kinases of recent discovery. They interact with homeobox proteins and other transcription factors, as well as transcriptional coactivators or corepressors depending on the cellular context. HIPK proteins are sensors for various extracellular stimuli, which control key cellular functions such as signal transduction to downstream effectors that regulate apoptosis, embryonic development, DNA-damage response, and cellular proliferation. Thus, HIPKs are involved in proliferative diseases such as cancer and fibrosis. mRNA levels and protein stability tightly regulate expression levels of HIPKs. METHODS: Here, we review recent works investigating the regulation of HIPKs expression by microRNAs (miRNAs) that are involved in the control of cell proliferation, sensitivity to chemotherapeutic drugs, epithelial-mesenchymal transition, and glucose-stimulated insulin secretion. CONCLUSION: It appears that HIPK family members, and their related miRNAs, may be considered as novel therapeutic targets for treating cancer, renal fibrosis and type 2 diabetes.


Assuntos
Núcleo Celular/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose , Núcleo Celular/genética , Núcleo Celular/patologia , Dano ao DNA , Desenvolvimento Embrionário/genética , Transição Epitelial-Mesenquimal/genética , Fibrose/genética , Fibrose/metabolismo , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
14.
Oncotarget ; 6(19): 17342-53, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26009897

RESUMO

The mitotic spindle assembly checkpoint (SAC) is an essential control system of the cell cycle that contributes to mantain the genomic stability of eukaryotic cells. SAC genes expression is often deregulated in cancer cells, leading to checkpoint impairment and chromosome instability. The mechanisms responsible for the transcriptional regulation and deregulation of these genes are still largely unknown. Herein we identify the nonhistone architectural nuclear proteins High Mobility Group A1 (HMGA1), whose overexpression is a feature of several human malignancies and has a key role in cancer progression, as transcriptional regulators of SAC genes expression. In particular, we show that HMGA1 proteins are able to increase the expression of the SAC genes Ttk, Mad2l1, Bub1 and Bub1b, binding to their promoter regions. Consistently, HMGA1-depletion induces SAC genes downregulation associated to several mitotic defects. In particular, we observed a high number of unaligned chromosomes in metaphase, a reduction of prometaphase time, a delay of anaphase, a higher cytokinesis time and a higher percentage of cytokinesis failure by using live-cell microscopy. Finally, a significant direct correlation between HMGA1 and SAC genes expression was detected in human colon carcinomas indicating a novel mechanism by which HMGA1 contributes to cancer progression.


Assuntos
Instabilidade Cromossômica/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas HMGB/genética , Pontos de Checagem da Fase M do Ciclo Celular/genética , Animais , Western Blotting , Imunoprecipitação da Cromatina , Imunofluorescência , Células HeLa , Humanos , Imuno-Histoquímica , Camundongos , Células NIH 3T3 , Reação em Cadeia da Polimerase , Transfecção
15.
Infez Med ; 20(3): 145-54, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22992554

RESUMO

Streptococcus anginosus group is widely known for its ability to cause invasive pyogenic infections. There are very few reports of disseminated infections sustained by members of this streptococcal group. We report a case of a highly disseminated infection and analyse previous literature reports. Disseminated pyogenic infection has been defined as an infection affecting two or more of the following organs/systems: central nervous system, lung, liver and spleen. We performed a PubMed search using the terms: S. milleri, S. anginosus, brain abscess, pulmonary abscess, hepatic abscess, spleen abscess. We reviewed 12 case reports including the one presented in this paper. Underlying conditions such as dental infections, malignancy, gastrointestinal and respiratory tract disease accounted for 42% of cases. No definite endocarditis was encountered, even though positive blood cultures were found in 67% of patients. Concomitant brain-liver, brain-lung and brain-spleen involvement occurred in 50%, 42% and 8% of cases respectively. Ninety-one percent (91%) of patients were treated with ß-lactams, and surgical procedures were performed in 67% of patients. Infections caused by S. anginosus group members are satisfactorily treated with penicillin G and cephalosporins. It is very important to associate surgery to antimicrobial chemotherapy in order to achieve a full or nearly full clinical recovery.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/terapia , Streptococcus anginosus , Sucção , Bacteriemia/diagnóstico , Bacteriemia/terapia , Abscesso Encefálico/microbiologia , Abscesso Encefálico/terapia , Terapia Combinada , Empiema Pleural/microbiologia , Empiema Pleural/terapia , Hepatomegalia/microbiologia , Humanos , Abscesso Hepático/microbiologia , Abscesso Hepático/terapia , Abscesso Pulmonar/microbiologia , Abscesso Pulmonar/terapia , Masculino , Pessoa de Meia-Idade , Esplenomegalia/microbiologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/cirurgia , Streptococcus anginosus/isolamento & purificação , Streptococcus anginosus/patogenicidade , Streptococcus milleri (Grupo)/isolamento & purificação , Streptococcus milleri (Grupo)/patogenicidade , Resultado do Tratamento
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