RESUMEN
P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53. One of the explanations to this is that p53 is suppressed by overexpression of p53-specific E3-ubiquitin ligases: Mdm2, MdmX, Pirh2 and Cop1. Pharmacological inhibition of protein-protein interactions between p53 and these negative regulators is a promising therapeutic approach to treat cancers retaining wild type p53. To date, a series of chemical inhibitors of p53 interactions with Mdm2 and MdmX E3-ubiquitin ligases have been discovered and characterized. Several of them are in the early stages of clinical trials. Despite this fact, their clinical efficacy may be hampered by a number of reasons, including tumor-specific expression of multiple isoforms of the target E3-ligases, which become inert to treatment with small molecules. This and other biochemical mechanisms of possible resistance of tumor cells with wild type p53 to small molecules against its negative regulators will be discussed in this review.
Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias/tratamiento farmacológico , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Proteínas de Ciclo Celular , Humanos , Imidazoles/farmacología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Piperazinas/farmacología , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Transcription factor p63 is a member of the p53 protein family. Due to the high degree of structural similarity p53, p63, and p73 are known to have overlapping functions relating to cell cycle regulation, apoptosis and tumor transformation. Furthermore, p63 plays crucial role in epidermal tissue development and differentiation. Pirh2 (product of RCHY1 gene) is an E3 ubiquitin ligase modifying all three members of the p53 family resulting in their subsequent proteasomal degradation. Our results demonstrate that p63, similar to p53, is able to regulate expression levels of Pirh2. Importantly, Pirh2 expression is activated only by transcriptionally active isoform of p63--TAp63, but not the N-terminally truncated ΔNp63.
Asunto(s)
Regulación de la Expresión Génica , Complejo de la Endopetidasa Proteasomal/metabolismo , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina/genética , Secuencia de Aminoácidos , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Diferenciación Celular , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HCT116 , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Unión Proteica , Proteolisis , Eliminación de Secuencia , Transducción de Señal , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Transcripción Genética , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Genetic reprogramming by ectopic expression of transcription factor genes induces the pluripotent state in somatic cells. This technology provides an opportunity to establish pluripotent stem cells for each person, as well as to get better understanding of epigenetic mechanisms controlling cell state. Interestingly, some of the molecular processes that accompany somatic cell reprogramming in vitro are also characteristic for tumor manifestation. Thus, similar "molecular barriers" that control the stability of epigenetic state exist for both processes of pluripotency induction and malignant transformation. The reprogramming of tumor cells is interesting in two aspects: first, it will determine the contribution of epigenetic changes in carcinogenesis; second, it gives an approach to evaluate tumor stem cells that are supposed to form the entire cell mass of the tumor. This review discusses the key stages of genetic reprogramming, the similarity and difference between the reprogramming process and malignant transformation.
Asunto(s)
Reprogramación Celular/genética , Ingeniería Genética/métodos , Animales , Apoptosis/genética , Genes Supresores de Tumor , Humanos , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Respiration hydrogen analyzer H2Rate has been used in pilot examinations of a group of students. This method for noninvasive diagnosis of small intestinal diseases promotes proper interpretation of the results. Free hydrogen level in the exhaled air increases as a result of lactulose (diagnostic agent) cleavage by enteric microflora within about 3 h. Based on the experimental data, the main groups with characteristic curves reflecting the time course of hydrogen concentrations have been distinguished. Excessive bacterial colonization of the intestine can correspond to emergence of characteristic peaks of hydrogen concentrations in the curve. Hydrogen concentrations in exhaled air can also be analyzed to evaluate the rate of the substrate propulsion in the middle compartment of the intestine.
Asunto(s)
Hidrógeno/metabolismo , Intestino Delgado/microbiología , Adolescente , Adulto , Pruebas Respiratorias , Espiración , Humanos , Lactulosa/metabolismo , Microbiota , Proyectos Piloto , Adulto JovenRESUMEN
The incidence of Helicobacter pylori infection is analyzed by the results of screening of first- and fourth-year students of Moscow Institute of Foreign Affairs using HelicoSense Scientific breath test system. Age-related dynamics of the infection in patients examined for the first time has been traced. The data on infection rates in patients after eradication therapy are presented.
Asunto(s)
Pruebas Respiratorias/métodos , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Factores de Edad , Técnicas Electroquímicas/métodos , Femenino , Humanos , Inmunoensayo , Incidencia , Masculino , Prevalencia , Federación de Rusia/epidemiología , Adulto JovenRESUMEN
The genetic reprogramming technology allows one to generate pluripotent stem cells for individual patients. These cells, called induced pluripotent stem cells (iPSCs), can be an unlimited source of specialized cell types for the body. Thus, autologous somatic cell replacement therapy becomes possible, as well as the generation of in vitro cell models for studying the mechanisms of disease pathogenesis and drug discovery. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that leads to a loss of upper and lower motor neurons. About 10% of cases are genetically inherited, and the most common familial form of ALS is associated with mutations in the SOD1 gene. We used the reprogramming technology to generate induced pluripotent stem cells with patients with familial ALS. Patient-specific iPS cells were obtained by both integration and transgene-free delivery methods of reprogramming transcription factors. These iPS cells have the properties of pluripotent cells and are capable of direct differentiation into motor neurons.