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1.
Blood ; 120(24): 4846-9, 2012 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-23074272

RESUMEN

Although a role for oncogenic KIT in driving mast cell disease is clear, the mechanisms driving the multiple phenotypic and clinical manifestations of this disorder are not well elucidated. We now show, using a large cohort of mastocytosis patients, including an almost equal number of aggressive and nonaggressive cases of systemic mastocytosis, that in contrast to the oncogenic KITD816V, TET2 mutation statistically associates with aggressive forms of the disease. By infecting primary murine bone marrow-derived mast cells with KITD816V, we also observe a significant and competitive growth advantage for KITD816V in Tet2-nullizygous compared with wild-type cells. TET2-deficient cells display increased proliferation and can survive in the absence of cytokines. Taken together, these data demonstrate a oncogenic cooperation in mast cells and reveal TET2 mutation as a potential marker to diagnose and predict severe forms of mastocytosis.


Asunto(s)
Proteínas de Unión al ADN/genética , Mastocitos/metabolismo , Mastocitosis/genética , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Animales , Células de la Médula Ósea/metabolismo , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Células Cultivadas , Estudios de Cohortes , Dioxigenasas , Femenino , Humanos , Masculino , Mastocitos/patología , Mastocitosis/patología , Ratones , Ratones Noqueados , Persona de Mediana Edad , Factores de Tiempo , Transfección
2.
Haematologica ; 99(5): 830-5, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24389310

RESUMEN

Mastocytosis is a rare and chronic disease with phenotypes ranging from indolent to severe. Prognosis for this disease is variable and very few biomarkers to predict disease evolution or outcome are currently known. We have performed comprehensive screening in our large cohort of mastocytosis patients for mutations previously found in other myeloid diseases and that could serve as prognostic indicators. KIT, SRSF2-P95 and TET2 mutations were by far the most frequent, detected in 81%, 24% and 21% of patients, respectively. Where TET2 and SRSF2-P95 mutation both correlated with advanced disease phenotypes, SRSF2-P95 hotspot mutation was found almost exclusively in patients diagnosed with associated clonal hematologic non-mast cell disease. Statistically, TET2 and SRSF2-P95 mutations were highly associated, suggesting a mechanistic link between these two factors. Finally, analysis of both clonal and sorted cell populations from patients confirms the presence of these mutations in the mast cell component of the disease, suggests an ontological mutation hierarchy and provides evidence for the expansion of multiple clones. This highlights the prognostic potential of such approaches, if applied systematically, for delineating the roles of specific mutations in predisposing and/or driving distinct disease phenotypes.


Asunto(s)
Epigénesis Genética , Mastocitosis/genética , Mastocitosis/patología , Mutación , Proteínas Nucleares/genética , Ribonucleoproteínas/genética , Evolución Clonal/genética , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Humanos , Masculino , Mastocitos/metabolismo , Mastocitos/patología , Mastocitosis/mortalidad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit/genética , Factores de Empalme Serina-Arginina
3.
Brain Behav Immun ; 35: 51-7, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23917070

RESUMEN

BACKGROUND: Mastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis. OBJECTIVE: To demonstrate a possible relationship between negative emotionality in mastocytosis and leukocytes telomere length. METHODS: Leukocyte telomere length and telomerase activity were measured among mastocytosis patients and were correlated with perceived stress and depression assessed by the Beck Depression Inventory revised and the Perceived Stress Scale. RESULTS: Mild-severe depression scores were frequent (78.9%) as well as high perceived stress (42.11%). Telomere length was correlated to perceived stress (r=0.77; p=0.0001) but not to depression in our population. Patients displaying Wild-type KIT significantly presented higher perceived stress levels. Patients with the D816VC KIT mutation who had high perceived stress scores displayed significantly shorter telomere but not if they had high depression scores. CONCLUSION: These findings suggest that high perceived stress in mastocytosis could accelerate the rate of leukocytes telomere shortening. Since mastocytosis is, by definition, a mast cell mediated disease; these cells could be involved in this phenomenon. Mechanistic causal relationships between these parameters need to be investigated.


Asunto(s)
Depresión/genética , Mastocitosis/genética , Mastocitosis/psicología , Estrés Psicológico/genética , Acortamiento del Telómero , Adulto , Anciano , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Adulto Joven
4.
J Allergy Clin Immunol ; 132(4): 866-73.e1-3, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23890756

RESUMEN

BACKGROUND: Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in 1 or more organs. Gastrointestinal manifestations of systemic mastocytosis have been previously studied in small cohorts of patients, and no specific histologic description is available. OBJECTIVE: We sought to assess the clinical and pathologic features of gastrointestinal manifestations in patients with mastocytosis. METHODS: Medical history and gastrointestinal symptoms of patients with mastocytosis (n = 83) were compared with those of matched healthy subjects (n = 83) by means of patient questionnaire. Data were analyzed for epidemiologic, clinical, biological, and genetic factors associated with gastrointestinal symptoms for patients with mastocytosis. A comparative analysis of gastrointestinal histology from patients with mastocytosis (n = 23), control subjects with inflammatory bowel disease (n = 17), and healthy subjects (n = 19) was performed. RESULTS: The following gastrointestinal symptoms occurred more frequently and were more severe in patients with mastocytosis than in healthy subjects: bloating (33% vs 7.2%, P < .0001), abdominal pain (27.3% vs 4.8%, P < .0001), nausea (23% vs 8.4%, P = .02), and diarrhea (33.85% vs 1.2%, P < .0001). Patients with mastocytosis had a significantly higher incidence of personal history of duodenal ulcer (P = .02). Wild-type (WT) c-Kit was associated with diarrhea (P = .03). Specific histologic lesions were present in patients with mastocytosis but were not correlated with clinical symptoms. CONCLUSION: Gastrointestinal manifestations in patients with mastocytosis are highly prevalent and often severe. Clinical symptoms do not correspond to histologic findings, are nonspecific, and can simulate irritable bowel syndrome.


Asunto(s)
Enfermedades Gastrointestinales/patología , Enfermedades Gastrointestinales/fisiopatología , Mastocitosis Sistémica/patología , Adulto , Biopsia , Estudios de Casos y Controles , Diarrea/metabolismo , Diarrea/fisiopatología , Femenino , Enfermedades Gastrointestinales/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Humanos , Masculino , Mastocitosis Sistémica/inmunología , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/metabolismo , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios
5.
JCI Insight ; 7(7)2022 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-35393954

RESUMEN

Mutation of the TET2 DNA-hydroxymethylase has been associated with a number of immune pathologies. The disparity in phenotype and clinical presentation among these pathologies leads to questions regarding the role of TET2 mutation in promoting disease evolution in different immune cell types. Here we show that, in primary mast cells, Tet2 expression is induced in response to chronic and acute activation signals. In TET2-deficient mast cells, chronic activation via the oncogenic KITD816V allele associated with mastocytosis, selects for a specific epigenetic signature characterized by hypermethylated DNA regions (HMR) at immune response genes. H3K27ac and transcription factor binding is consistent with priming or more open chromatin at both HMR and non-HMR in proximity to immune genes in these cells, and this signature coincides with increased pathological inflammation signals. HMR are also associated with a subset of immune genes that are direct targets of TET2 and repressed in TET2-deficient cells. Repression of these genes results in immune tolerance to acute stimulation that can be rescued with vitamin C treatment or reiterated with a Tet inhibitor. Overall, our data support a model where TET2 plays a direct role in preventing immune tolerance in chronically activated mast cells, supporting TET2 as a viable target to reprogram the innate immune response for innovative therapies.


Asunto(s)
Proteínas de Unión al ADN , Dioxigenasas , Tolerancia Inmunológica , Mastocitos , Proteínas de Unión al ADN/metabolismo , Dioxigenasas/metabolismo , Mastocitos/inmunología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo
6.
Science ; 351(6274): aad5510, 2016 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-26797145

RESUMEN

Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells.


Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Células Madre Embrionarias/citología , Elementos de Facilitación Genéticos/fisiología , Regulación de la Expresión Génica , Macrófagos/citología , Animales , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Redes Reguladoras de Genes , Factor de Transcripción MafB/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-maf/metabolismo , Análisis de la Célula Individual , Activación Transcripcional
7.
Medicine (Baltimore) ; 95(24): e3901, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27310990

RESUMEN

Mastocytosis is a heterogeneous group of diseases with a young median age at diagnosis. Usually indolent and self-limited in childhood, the disease can exhibit aggressive progression in mid-adulthood. Our objectives were to describe the characteristics of the disease when diagnosed among elderly patients, for which rare data are available.The French Reference Center conducted a retrospective multicenter study on 53 patients with mastocytosis >69 years of age, to describe their clinical, biological, and genetic features.The median age of our cohort of patients was 75 years. Mastocytosis variants included were cutaneous (n = 1), indolent systemic (n = 5), aggressive systemic (n = 11), associated with a hematological non-mast cell disease (n = 34), and mast cell leukemia (n = 2). Clinical manifestations were predominantly mast cell activation symptoms (75.5%), poor performance status (50.9%), hepatosplenomegaly (50.9%), skin involvement (49.1%), osteoporosis (47.2%), and portal hypertension and ascites (26.4%). The main biological features were anemia (79.2%), thrombocytopenia (50.9%), leucopenia (20.8%), and liver enzyme abnormalities (32.1%). Of the 40 patients tested, 34 (85%), 2 (5%), and 4 (10%) exhibited the KIT D816V mutant, other KIT mutations and the wild-type form of the KIT gene, respectively. Additional sequencing detected significant genetic defects in 17 of 26 (65.3%) of the patients with associated hematological non-mast cell disease, including TET2, SRSF2, IDH2, and ASLX1 mutations. Death occurred in 19 (35.8%) patients, within a median delay of 9 months, despite the different treatment options available.Mastocytosis among elderly patients has a challenging early detection, rare skin involvement, and/or limited skin disease; it is heterogeneous and has often an aggressive presentation with nonfortuitous associated myeloid lineage malignant clones, and thus a poor overall prognosis.


Asunto(s)
ADN de Neoplasias/genética , Mastocitos/patología , Mastocitosis/epidemiología , Mutación , Oncogenes/genética , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Francia/epidemiología , Humanos , Masculino , Mastocitos/metabolismo , Mastocitosis/diagnóstico , Mastocitosis/genética , Morbilidad/tendencias , Estudios Retrospectivos
8.
Adv Cancer Res ; 84: 81-154, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11885563

RESUMEN

The activated product of the myc oncogene deregulates both cell growth and death check points and, in a permissive environment, rapidly accelerates the affected clone through the carcinogenic process. Advances in understanding the molecular mechanism of Myc action are highlighted in this review. With the revolutionary developments in molecular diagnostic technology, we have witnessed an unprecedented advance in detecting activated myc in its deregulated, oncogenic form in primary human cancers. These improvements provide new opportunities to appreciate the tumor subtypes harboring deregulated Myc expression, to identify the essential cooperating lesions, and to realize the therapeutic potential of targeting Myc. Knowledge of both the breadth and depth of the numerous biological activities controlled by Myc has also been an area of progress. Myc is a multifunctional protein that can regulate cell cycle, cell growth, differentiation, apoptosis, transformation, genomic instability, and angiogenesis. New insights into Myc's role in regulating these diverse activities are discussed. In addition, breakthroughs in understanding Myc as a regulator of gene transcription have revealed multiple mechanisms of Myc activation and repression of target genes. Moreover, the number of reported Myc regulated genes has expanded in the past few years, inspiring a need to focus on classifying and segregating bona fide targets. Finally, the identity of Myc-binding proteins has been difficult, yet has exploded in the past few years with a plethora of novel interactors. Their characterization and potential impact on Myc function are discussed. The rapidity and magnitude of recent progress in the Myc field strongly suggests that this marvelously complex molecule will soon be unmasked.


Asunto(s)
Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/fisiología , Animales , Apoptosis , Ciclo Celular , Cromatina/metabolismo , Humanos , Modelos Biológicos , Neoplasias/genética , Neovascularización Patológica , Isoformas de Proteínas , Transcripción Genética
9.
Mol Immunol ; 63(1): 55-60, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24768320

RESUMEN

Mastocytosis is an incurable and sometimes fatal haematological disorder grossly described as the accumulation of abnormal mast cells in the bone marrow and other organs causing tissue and organ damage. The clinical manifestations of this disease are extremely variable; disease phenotypes range from indolent to aggressive, and often present with associated non-mast cell haematological disorders (AHNMD), mainly myeloproliferative neoplasm and myelodysplastic syndromes. Recent efforts to genetically dissect the mechanisms that define aggressive and non-aggressive mastocytosis have generated a list of recurrent somatic mutations in mastocytosis patients that are associated with and may predict the evolution towards aggressive disease phenotypes. Here we review these mutations and discuss the molecular mechanisms associated with these mutations in an effort to better understand the biology of this disease and to predict its onset and evolution, with the ultimate goal of devising new and improved treatment strategies.


Asunto(s)
Mastocitos/inmunología , Mastocitosis/genética , Proteínas de Unión al ADN/genética , Dioxigenasas , Humanos , Isocitrato Deshidrogenasa/genética , Mastocitosis/inmunología , Mutación , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit/genética , Factores de Empalme de ARN , Proteínas Represoras/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteínas/genética , Factores de Empalme Serina-Arginina , Factor de Empalme U2AF
10.
Immunol Allergy Clin North Am ; 34(2): 239-62, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24745672

RESUMEN

In all variants of mastocytosis, activating KIT mutations are frequently found. In adults, neoplastic mast cells (MCs) cells show the KIT mutation D816V, whereas in children, MCs invading the skin are frequently positive for non-KIT D816V mutations. The clinical course and prognosis of the disease vary among patients with systemic mastocytosis (SM). Additional KIT-independent molecular defects might cause progression. Additional oncogenic lesions have recently been identified in advanced SM. In advanced SM the presence of additional genetic lesions or altered signaling worsening the prognosis might lead to the use of alternative therapies such as combined antisignaling targeted treatments or stem cell transplantation.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Hematológicas/genética , Mastocitos/metabolismo , Mastocitosis/genética , Proteínas Proto-Oncogénicas c-kit/genética , Empalmosomas/genética , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Proliferación Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Exones , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Humanos , Mastocitos/efectos de los fármacos , Mastocitos/patología , Mastocitosis/diagnóstico , Mastocitosis/tratamiento farmacológico , Mastocitosis/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Empalmosomas/metabolismo , Empalmosomas/patología , Factor de Células Madre/genética , Factor de Células Madre/metabolismo
11.
PLoS One ; 9(1): e85362, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24465546

RESUMEN

Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS.


Asunto(s)
Proteínas de Unión al ADN/genética , Neoplasias Hematológicas/genética , Mastocitosis Sistémica/genética , Neutropenia/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Dioxigenasas , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/mortalidad , Persona de Mediana Edad , Monocitos/patología , Mutación , Neutropenia/complicaciones , Neutropenia/diagnóstico , Neutropenia/mortalidad , Pronóstico , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-kit/genética , Análisis de Supervivencia
13.
Science ; 326(5954): 867-71, 2009 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-19892988

RESUMEN

In metazoan organisms, terminal differentiation is generally tightly linked to cell cycle exit, whereas the undifferentiated state of pluripotent stem cells is associated with unlimited self-renewal. Here, we report that combined deficiency for the transcription factors MafB and c-Maf enables extended expansion of mature monocytes and macrophages in culture without loss of differentiated phenotype and function. Upon transplantation, the expanded cells are nontumorigenic and contribute to functional macrophage populations in vivo. Small hairpin RNA inactivation shows that continuous proliferation of MafB/c-Maf deficient macrophages requires concomitant up-regulation of two pluripotent stem cell-inducing factors, KLF4 and c-Myc. Our results indicate that MafB/c-MafB deficiency renders self-renewal compatible with terminal differentiation. It thus appears possible to amplify functional differentiated cells without malignant transformation or stem cell intermediates.


Asunto(s)
Proliferación Celular , Macrófagos/fisiología , Factor de Transcripción MafB/deficiencia , Proteínas Proto-Oncogénicas c-maf/deficiencia , Animales , Diferenciación Celular , Transformación Celular Neoplásica , Células Cultivadas , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/fisiología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/citología , Macrófagos/trasplante , Factor de Transcripción MafB/genética , Factor de Transcripción MafB/fisiología , Ratones , Ratones Noqueados , Monocitos/citología , Monocitos/fisiología , Células Progenitoras Mieloides/citología , Células Progenitoras Mieloides/fisiología , Fagocitosis , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/fisiología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/fisiología , Regulación hacia Arriba
14.
EMBO J ; 24(12): 2096-103, 2005 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-15920484

RESUMEN

Bax promotes cell death by permeabilizing mitochondrial outer membranes by an unresolved mechanism. However, in cells lacking the gene c-myc, membrane permeabilization by Bax is blocked by changes in the mitochondria that prevent Bax oligomerization. Drug-treated c-myc null cells and cells expressing Myc were used to map the topology of Bax in membranes prior to and after mitochondrial permeabilization. Chemical labeling of single cysteine mutants of Bax using a membrane bilayer impermeant cysteine-specific modifying agent revealed that Bax inserted both the 'pore domain' (helices alpha5-alpha6), and the tail-anchor (helix alpha9) into membranes prior to oligomerization and membrane permeabilization. Additional topology changes for Bax were not required in Myc-expressing cells to promote oligomerization and cytochrome c release. Our results suggest that unlike most pore-forming proteins, Bax membrane permeabilization results from oligomerization of transmembrane monomers rather than concerted insertion of the pore domains of a preformed oligomer.


Asunto(s)
Apoptosis/fisiología , Membranas Intracelulares/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Proteínas Portadoras/metabolismo , Cisteína/genética , Cisteína/metabolismo , Citocromos c/metabolismo , Humanos , Immunoblotting , Mitocondrias/metabolismo , Mutación , Permeabilidad , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína X Asociada a bcl-2
15.
EMBO J ; 22(20): 5459-70, 2003 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-14532118

RESUMEN

Bcl-x(L) and Bcl-2 inhibit both apoptosis and proliferation. In investigating the relationship between these two functions of Bcl-x(L) and Bcl-2, an analysis of 24 Bcl-x(L) and Bcl-2 mutant alleles, including substitutions at residue Y28 previously reported to selectively abolish the cell cycle activity, showed that cell cycle delay and anti-apoptosis co-segregated in all cases. In determining whether Bcl-2 and Bcl-x(L) act in G(0) or G(1), forward scatter and pyronin Y fluorescence measurements indicated that Bcl-2 and Bcl-x(L) cells arrested more effectively in G(0) than controls, and were delayed in G(0)-G(1) transition. The cell cycle effects of Bcl-2 and Bcl-x(L) were reversed by Bad, a molecule that counters the survival function of Bcl-2 and Bcl-x(L). When control and Bcl-x(L) cells of equivalent size and pyronin Y fluorescence were compared, the kinetics of cell cycle entry were similar, demonstrating that the ability of Bcl-x(L) and Bcl-2 cells to enhance G(0) arrest contributes significantly to cell cycle delay. Our data suggest that cell cycle effects and increased survival both result from intrinsic functions of Bcl-2 and Bcl-x(L).


Asunto(s)
Apoptosis/fisiología , Ciclo Celular/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Alelos , Animales , Proteínas Portadoras/metabolismo , División Celular , Línea Celular , Inhibición de Contacto , Fase G1 , Cinética , Mutagénesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas , Proteínas Recombinantes/metabolismo , Fase de Descanso del Ciclo Celular , Proteína Letal Asociada a bcl , Proteína bcl-X
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