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BACKGROUND: Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce. AIMS: We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity. METHODS: We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded. RESULTS: Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found. CONCLUSION: Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.
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Encéfalo , Circulación Cerebrovascular , Imagen por Resonancia Magnética , Talasemia beta , Humanos , Talasemia beta/fisiopatología , Talasemia beta/patología , Masculino , Femenino , Adulto , Estudios Transversales , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Adulto Joven , Circulación Cerebrovascular/fisiología , Adolescente , Persona de Mediana Edad , NiñoRESUMEN
Among pro-inflammatory cytokines, Interleukin-1ß is crucially involved in several inflammatory-based diseases and even cancer. Increased Interleukin-1ß levels in oral fluids have been proposed as an early marker of periodontitis, a broadly diffused chronic inflammatory condition of periodontal-supporting tissues, leading eventually to tooth loss. We describe the development of a portable surface-plasmon-resonance-based optical fiber probe suitably coated with an anti-Interleukin-1ß antibody monolayer. A pico-nanomolar linear range of determination was obtained in both buffer solution and saliva with a rapid (3 min) incubation and high selectivity in presence of interferents. Higher Interleukin-1ß concentration in the saliva of a periodontitis patient compared to a healthy control was determined. These measurements were validated by an automated ELISA system. Our results sustain the potential applicability of the proposed SPR-POF as diagnostic point-of-care device for real-time monitoring of salivary Interleukin-1ß, that can support early detection of oral inflammatory-based pathologies and rapid and timely therapeutic decisions.
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The analysis of salivary biomarkers as expression of periodontal health conditions has been proposed as a useful aid to conventional diagnostic approaches. In this study, we present a point-of-care test (POCT) exploiting a surface plasmon resonance (SPR)-based optical biosensor to detect salivary macrophage inflammatory protein (MIP)-1α, a promising marker of periodontitis. A plastic optical fiber (POF) was suitably modified and functionalized by an antibody self-assembled monolayer against MIP-1α for plasmonic detection. The proposed SPR-POF biosensor showed high selectivity and very low limit of detection for MIP-1α of 129 fM (1.0 pg/mL) in phosphate-buffered saline and 346 fM (2.7 pg/mL) in saliva. As a proof of concept, this POCT was also able to discriminate between a periodontitis patient and a healthy subject. The obtained results support the future application of this technology for an on-site detection and real-time monitoring of periodontal health conditions for diagnostic and therapeutic purposes.
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The precise characterization of oxygen-sensing pathways and the identification of pO2-regulated gene expression are both issues of critical importance. The O2-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
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Edición Génica , Neoplasias , Humanos , Hipoxia/genética , Oxígeno/metabolismo , Hipoxia de la Célula/genética , Neoplasias/genética , Neoplasias/terapia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Microambiente Tumoral/genéticaRESUMEN
OBJECTIVES: The evaluation of salivary biomarkers has been proposed as a simple and non-invasive aid to the conventional periodontal diagnosis based on clinical-radiographic parameters. Matrix metalloproteinase-8 (MMP-8), especially in its active form, is considered one of the most reliable biomarkers of periodontitis, and point-of-care tests (POCTs) have been proposed for its clinical monitoring. In this proof-of-concept study, a novel highly sensitive POCT based on a plastic optical fiber (POF) biosensor exploiting surface plasmon resonance (SPR) to detect salivary MMP-8 is described. METHODS: A SPR-POF biosensor was functionalized with a specific antibody to develop a surface-assembled monolayer (SAM) for the detection of total MMP-8. A white light source and a spectrometer connected to the biosensor were used to quantify MMP-8 level in both buffer and real matrix (saliva) by analysing the shift of the resonance wavelength determined by the specific antigen-antibody binding upon the SAM. RESULTS: Dose-response curves by serial dilutions of human recombinant MMP-8 were realized, obtaining a limit of detection (LOD) of 40 pM (1.76 ng/ml) in buffer and 225 pM (9.9 ng/ml) in saliva and high selectivity compared to interferent analytes (MMP-2 and IL-6). CONCLUSIONS: The proposed optical fiber-based POCT was able to detect and measure total MMP-8 with high selectivity and very low LOD in both buffer and saliva. CLINICAL SIGNIFICANCE: The SPR-POF technology may be employed to create highly sensitive biosensors to monitor salivary MMP-8 levels. The possibility of specifically detecting its active, rather than total, form need to be further investigated. If confirmed and clinically validated, such a device may represent a promising tool to make an immediate, highly sensitive and reliable diagnosis of periodontitis, and to carry out a timely and targeted therapy, possibly helping to prevent the onset of local and systemic periodontitis-related complications.
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Biomarcadores , Técnicas Biosensibles , Metaloproteinasa 8 de la Matriz , Enfermedades Periodontales , Saliva , Humanos , Metaloproteinasa 8 de la Matriz/análisis , Saliva/química , Técnicas Biosensibles/métodos , Enfermedades Periodontales/patología , Biomarcadores/análisisRESUMEN
Numerous pieces of evidence demonstrate that oxidative stress impairs biological functions, speeds up aging, and has a role in a variety of human diseases, including systemic and oral inflammatory disorders, and even cancer. Therefore, technologies providing accurate measures of oxidative stress indicators or biomarkers appear essential in the identification/prevention of such diseases, and in their management. Particularly advantageous is the employement of point-of-care tests based on affordable and small biochips since they can quickly process biological samples and deliver results near the point of care for a prompt therapeutic intervention. Malondialdehyde (MDA) is a key byproduct of oxidative reaction and has been identified as an effective marker of oxidative stress. Herein, we describe the detection of MDA in buffer and in a complex matrix such as saliva, using a plasmonic optical fiber device combined with a highly selective anti-MDA antibody. The experimental results highlight the excellent performance of the proposed biosensor, as well as its ability to provide a low-cost point-of-care test (PoC-T) to be used in real life situations. We demonstrated that a single saliva dilution step and a short incubation time are required for the accurate detection of low concentrations of total MDA (free and conjugated). As a proof-of-concept of future biomedical applications, the method has been tested to determine MDA concentration in saliva of a periodontitis patient compared to that of a healthy control. The obtained findings represent the basis for developing PoC-Ts to be employed in monitoring oral diseases like periodontitis, oral cancers or systemic oxidative-stress associated pathologies. Conclusively, our study puts the ground for an oxidative stress biosensor widely-applicable to different scenarios.
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Técnicas Biosensibles , Periodontitis , Humanos , Malondialdehído , Sistemas de Atención de Punto , Fibras Ópticas , Estrés Oxidativo , BiomarcadoresRESUMEN
Point-of-Care tests based on biomarkers, useful to monitor acute and chronic inflammations, are required for advances in medicine. In this scope, a key role is played by pro-inflammatory cytokines, of which interleukin 6 (IL-6) is generally thought as one of the most relevant. To use IL-6 in real scenarios, detection in ultra-low concentration ranges is required. In this work, two IL-6 biosensors are obtained by exploiting the combination of the same antibody self-assembled monolayer with two different plasmonic probes. This approach has demonstrated, via experimental results, that two different IL-6 concentration ranges can be explored. More specifically, IL-6 in an atto-femto molar range can be detected via polymer-based nanoplasmonic chips. On the other hand, a pico-nano molar range is obtained by a surface plasmon resonance platform in plastic optical fibers. As a proof of concept, the detection of IL-6 at the femto molar range has been obtained in Saliva and Serum. The results show that the proposed sensing approach could be useful in developing Point-of-Care devices based on a general setup with the capability to exploit both the plasmonic biosensor chips to monitor the IL-6 in the concentration range of interest, to provide an important support for the diagnosis and monitoring of oral and systemic diseases.
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Técnicas Biosensibles , Interleucina-6 , Polimetil Metacrilato , Técnicas Biosensibles/métodos , Resonancia por Plasmón de Superficie , Pruebas en el Punto de AtenciónRESUMEN
BACKGROUND: At the end of 2019 a new respiratory syndrome emerged in China named Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection. Considering the severity of the disease in adult subjects with one or more chronic pathologies, it was mandatory to find simple and effective biomarkers for negative prognosis of the disease easily available at the admission to the hospital. METHODS: To identify possible parameters showing association with the outcome in COVID-19 patients with pre-existing chronic diseases, blood biochemical profiles of 511 patients, enrolled from March to June 2020, were retrospectively evaluated. The pathological conditions taken into consideration were diabetes, arterial hypertension, chronic kidney disease, cardiovascular diseases, chronic obstructive pulmonary disease, obesity, and cancer. All the data were collected upon admission to the emergency room (ER) during the indicated period. RESULTS: We observed that serum and ionized calcium were prevalently altered in our cohort. We determined that hypocalcemia was a major parameter associated with mechanical ventilation and poor prognosis, correlating also with the presence of comorbidities such as cardiovascular diseases, chronic kidney disease, and cancer. In addition, we found a positive correlation between hypocalcemia and clinical complications during hospitalizations. CONCLUSIONS: Our results strengthen the relevance of serum calcium concentration as a useful prognostic biomarker in hospitalized COVID-19 patients.
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COVID-19 , Enfermedades Cardiovasculares , Hipocalcemia , Adulto , Humanos , SARS-CoV-2 , Estudios Retrospectivos , Hipocalcemia/diagnóstico , Calcio , BiomarcadoresRESUMEN
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors' (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control.
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Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , ARN Largo no Codificante , Quinasas Ciclina-Dependientes/metabolismo , Humanos , ARN Largo no Codificante/genéticaRESUMEN
The Cyclin-dependent kinase (CDK) regulator p27Kip1 is a gatekeeper of G1/S transition. It also regulates G2/M progression and cytokinesis completion, via CDK-dependent or -independent mechanisms. Recently, other important p27Kip1 functions have been described, including the regulation of cell motility and migration, the control of cell differentiation program and the activation of apoptosis/autophagy. Several factors modulate p27Kip1 activities, including its level, cellular localization and post-translational modifications. As a matter of fact, the protein is phosphorylated, ubiquitinated, SUMOylated, O-linked N-acetylglicosylated and acetylated on different residues. p27Kip1 belongs to the family of the intrinsically unstructured proteins and thus it is endowed with a large flexibility and numerous interactors, only partially identified. In this review, we look at p27Kip1 properties and ascribe part of its heterogeneous functions to the ability to act as an anchor or scaffold capable to participate in the construction of different platforms for modulating cell response to extracellular signals and allowing adaptation to environmental changes.
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Ciclo Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas Intrínsecamente Desordenadas/metabolismo , Procesamiento Proteico-Postraduccional , Andamios del Tejido/química , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/química , Humanos , Proteínas Intrínsecamente Desordenadas/químicaRESUMEN
p57Kip2 protein is a member of the CIP/Kip family, mainly localized in the nucleus where it exerts its Cyclin/CDKs inhibitory function. In addition, the protein plays key roles in embryogenesis, differentiation, and carcinogenesis depending on its cellular localization and interactors. Mutations of CDKN1C, the gene encoding human p57Kip2, result in the development of different genetic diseases, including Beckwith-Wiedemann, IMAGe and Silver-Russell syndromes. We investigated a specific Beckwith-Wiedemann associated CDKN1C change (c.946 C>T) that results in the substitution of the C-terminal amino acid (arginine 316) with a tryptophan (R316W-p57Kip2). We found a clear redistribution of R316W-p57Kip2, in that while the wild-type p57Kip2 mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57Kip2 N- and C-terminal domain, respectively, allows the mapping of the nuclear localization signal(s) (NLSs) between residues 220-316. Moreover, by removing the basic RKRLR sequence at the protein C-terminus (from 312 to 316 residue), p57Kip2 was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57Kip2 NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57Kip2 localization/regulatory roles.
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Síndrome de Beckwith-Wiedemann/genética , Núcleo Celular/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Mutación , Señales de Localización Nuclear , Síndrome de Beckwith-Wiedemann/patología , Ciclo Celular , Núcleo Celular/genética , Proliferación Celular , Células HEK293 , Células Hep G2 , HumanosRESUMEN
CDKN1B haploinsufficiency promotes the development of several human cancers. The gene encodes p27Kip1 , a protein playing pivotal roles in the control of growth, differentiation, cytoskeleton dynamics, and cytokinesis. CDKN1B haploinsufficiency has been associated with chromosomal or gene aberrations. However, very few data exist on the mechanisms by which CDKN1B missense mutations facilitate carcinogenesis. Here, we report a functional study on a cancer-associated germinal p27Kip1 variant, namely glycine9->arginine-p27Kip1 (G9R-p27Kip1 ) identified in a parathyroid adenoma. We unexpectedly found that G9R-p27Kip1 lacks the major tumor suppressor activities of p27Kip1 including its antiproliferative and pro-apoptotic functions. In addition, G9R-p27Kip1 transfection in cell lines induces the formation of more numerous and larger spheres when compared to wild-type p27Kip1 -transfected cells. We demonstrated that the mutation creates a consensus sequence for basophilic kinases causing a massive phosphorylation of G9R-p27Kip1 on S12, a residue normally never found modified in p27Kip1 . The novel S12 phosphorylation appears responsible for the loss of function of G9R-p27Kip1 since S12AG9R-p27Kip1 recovers most of the p27Kip1 tumor suppressor activities. In addition, the expression of the phosphomimetic S12D-p27Kip1 recapitulates G9R-p27Kip1 properties. Mechanistically, S12 phosphorylation enhances the nuclear localization of the mutant protein and also reduces its cyclin-dependent kinase (CDK)2/CDK1 inhibition activity. To our knowledge, this is the first reported case of quantitative phosphorylation of a p27Kip1 variant on a physiologically unmodified residue associated with the loss of several tumor suppressor activities. In addition, our findings demonstrate that haploinsufficiency might be due to unpredictable post-translational modifications due to generation of novel consensus sequences by cancer-associated missense mutations.
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Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Genes Supresores de Tumor , Mutación con Pérdida de Función , Neoplasias/genética , Línea Celular Tumoral , Humanos , Mutación Missense , Fosforilación , Procesamiento Proteico-PostraduccionalRESUMEN
In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27Kip1 and p57Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols' activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27Kip1 and p57Kip2 in polyphenols' cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.
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Antineoplásicos Fitogénicos/farmacología , Catequina/análogos & derivados , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Neoplasias/tratamiento farmacológico , Resveratrol/farmacología , Catequina/farmacología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Dominios Proteicos , ProteolisisRESUMEN
The ongoing pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has so far infected about 2.42 × 107 (as at 27 August 2020) subjects with more than 820,000 deaths. It is the third zoonotic coronavirus-dependent outbreak in the last twenty years and represents a major infective threat for public health worldwide. A main aspect of the infection, in analogy to other viral infections, is the so-called "cytokine storm", an inappropriate molecular response to virus spread which plays major roles in tissue and organ damage. Immunological therapies, including vaccines and humanized monoclonal antibodies, have been proposed as major strategies for prevention and treatment of the disease. Accordingly, a detailed mechanistic knowledge of the molecular events with which the virus infects cells and induces an immunological response appears necessary. In this review, we will report details of the initial process of SARS-CoV-2 cellular entry with major emphasis on the maturation of the spike protein. Then, a particular focus will be devoted to describe the possible mechanisms by which dendritic cells, a major cellular component of innate and adaptive immune responses, may play a role in the spread of the virus in the human body and in the clinical evolution of the disease.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/virología , Células Dendríticas/virología , Neumonía Viral/virología , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Piroptosis , Sistema Renina-Angiotensina , SARS-CoV-2 , Internalización del VirusRESUMEN
Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.
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Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Daño del ADN , Litio/farmacología , Neuronas/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Litio/toxicidad , Neuronas/metabolismoRESUMEN
Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222CâA, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598CâT) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).
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Mutación de Línea Germinal , Trastornos del Crecimiento/genética , Hipoglucemia/genética , Factor 1 Inducible por Hipoxia/deficiencia , Mitocondrias/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Expresión Génica , Crecimiento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiología , Síndrome , Adulto JovenRESUMEN
The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases.
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Diferenciación Celular/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Epigenómica , Regulación de la Expresión Génica , Homeostasis/genética , Animales , HumanosAsunto(s)
Anemia Hipocrómica/genética , Proteínas de Transporte de Catión/genética , Mutación con Pérdida de Función , Mutación Missense , Anemia Hipocrómica/terapia , Transfusión Sanguínea , Exones/genética , Femenino , Heterocigoto , Humanos , Recién Nacido , Hierro/análisis , Sobrecarga de Hierro , Hígado/química , Miocardio/química , LinajeRESUMEN
p27Kip1 is a cell cycle regulator firstly identified as a cyclin-dependent kinase inhibitor. For a long time, its function has been associated to cell cycle progression inhibition at G1/S boundary in response to antiproliferative stimuli. The picture resulted complicated by the discovery that p27Kip1 is an intrinsically unstructured protein, with numerous CDK-dependent and -independent functions and involvement in many cellular processes, such as cytoskeleton dynamics and cell motility control, apoptosis and autophagy activation. Depending on the cell context, these activities might turn to be oncogenic and stimulate cancer progression and metastatization. Nevertheless, p27Kip1 role in cancer biology suppression was underscored by myriad data reporting its down-regulation and/or cytoplasmic relocalization in different tumors, while usually no genetic alterations were found in human cancers, making the protein a non-canonical oncosuppressor. Recently, mostly due to advances in genomic analyses, CDKN1B, p27Kip1 encoding gene, has been found mutated in several cancers, thus leading to a profound reappraisal of CDKN1B role in tumorigenesis. This review summarizes the main p27Kip1 features, with major emphasis to its role in cancer biology and to the importance of CDKN1B mutations in tumor development.