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1.
Pediatr Allergy Immunol ; 35(9): e14245, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39312287

RESUMEN

BACKGROUND: Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia. OBJECTIVE: To characterize the PI3K/AKT/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity. METHODS: We included 12 patients (heterozygous PIK3CD (n = 9) and PIK3R1 (n = 1) (activated PI3K delta syndrome (APDS) with gain-of-function mutations) and homozygous PIK3R1 variant (n = 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. RESULTS: Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5-37) in APDS. Median diagnostic delay was 12.9 years (1.6-27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non-Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late-onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss-of function mutations. CONCLUSION: Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.


Asunto(s)
Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Masculino , Niño , Adolescente , Preescolar , Transducción de Señal/genética , Femenino , Lactante , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Adulto , Adulto Joven , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Mutación
2.
J Clin Immunol ; 41(5): 992-1003, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33629196

RESUMEN

BACKGROUND: Chronic granulomatous disease (CGD), one of the phagocytic system defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex which generates reactive oxygen species (ROS), which are essential for killing pathogenic microorganisms, especially catalase-positive bacteria and fungi. OBJECTIVE: The objective of our study was to assess the clinical and laboratory characteristics, treatment modalities, and prognosis of patients with CGD. METHODS: We retrospectively reviewed 63 patients with CGD who have been diagnosed, treated, and/or followed-up between 1984 and 2018 in Hacettepe University, Ankara, in Turkey, as a developing country. RESULTS: The number of female and male patients was 26/37. The median age at diagnosis was 3.8 (IQR: 1.0-9.6) years. The rate of consanguinity was 63.5%. The most common physical examination finding was lymphadenopathy (44/63), growth retardation (33/63), and hepatomegaly (27/63). One adult patient had squamous cell carcinoma of the lung. The most common infections were lung infection (53/63), skin abscess (43/63), and lymphadenitis (19/63). Of the 63 patients with CGD, 6 patients had inflammatory bowel disease (IBD). Twelve of the 63 patients died during follow-up. CYBA, NCF1, CYBB, and NCF2 mutations were detected in 35%, 27.5%, 25%, and 12.5% of the patients, respectively. CONCLUSION: We identified 63 patients with CGD from a single center in Turkey. Unlike other cohort studies in Turkey, due to the high consanguineous marriage rate in our study group, AR form of CGD was more frequent, and gastrointestinal involvement were found at relatively lower rates. The rate of patients who treated with HSCT was lower in our research than in the literature. A majority of the patients in this study received conventional prophylactic therapies, which highlight on the outcome of individuals who have not undergone HSCT.


Asunto(s)
Enfermedad Granulomatosa Crónica/diagnóstico , Adolescente , Adulto , Consanguinidad , Femenino , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/inmunología , Enfermedad Granulomatosa Crónica/terapia , Humanos , Masculino , Mutación , NADPH Oxidasas/genética , Estudios Retrospectivos , Turquía , Adulto Joven
3.
J Clin Immunol ; 40(3): 494-502, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32056073

RESUMEN

Common variable immunodeficiency (CVID) results in defective B cell differentiation and impaired antibody production and is the most common symptomatic primary immunodeficiency. Our aim was to evaluate the correlation among B cell subgroups, κ-deleting recombination excision circle (KREC) copy numbers, and clinical and immunological data of the patients with CVID, and evaluate the patients according to classifications currently available to define the role of KREC copy numbers in the diagnosis of CVID. KREC analysis was performed using a quantitative real-time polymerase chain reaction assay, and B cell subgroups were measured by flow cytometry. The median age of the patients (n = 30) was 25 (6-69) years. Parental consanguinity ratio was 33%. The median age at diagnosis was 15 (4-59), and follow-up period was 6 (1-37) years. CD19+ and CD4+ cell counts at the time of diagnosis were low in 66.7% and 46.7% of the patients, respectively. CD19+ cell counts were positively correlated with KREC copy numbers in patients and healthy controls. CD19+ cell counts and KREC copy numbers were significantly reduced in CVID patients compared to healthy controls as expected. KRECs are quantitative markers for B cell defects. We found low CD4+ cell numbers, recent thymic emigrants, and lymphopenia in some of the patients at diagnosis, which reminds the heterogeneity of CVID's etiology. In this study, a positive correlation was shown between CD19+ cell counts and KREC copy numbers. Low KREC copy numbers indicated B cell deficiency; however, high KREC copy numbers were not sufficient to rule out CVID.


Asunto(s)
Linfocitos B/fisiología , Inmunodeficiencia Variable Común/inmunología , ADN Recombinante/genética , Cadenas kappa de Inmunoglobulina/genética , Subgrupos Linfocitarios/fisiología , Linfocitos T/fisiología , Adolescente , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos CD19/metabolismo , Niño , Preescolar , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/genética , Femenino , Citometría de Flujo , Humanos , Linfopenia , Masculino , Persona de Mediana Edad , Adulto Joven
4.
J Clin Immunol ; 39(7): 726-738, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31432443

RESUMEN

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/etiología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Síndrome Linfoproliferativo Autoinmune/complicaciones , Síndrome Linfoproliferativo Autoinmune/terapia , Biomarcadores , Niño , Preescolar , Terapia Combinada , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/terapia , Enfermedades Transmisibles/etiología , Femenino , Estudios de Asociación Genética/métodos , Sitios Genéticos , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Masculino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Secuenciación del Exoma , Adulto Joven
5.
Clin Immunol ; 161(2): 316-23, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26117625

RESUMEN

Combined immunodeficiencies (CIDs) are heterogeneous group of disorders characterized by abrogated/impaired T cell development and/or functions that resulted from diverse genetic defects. In addition to the susceptibility to infections with various microorganisms, the patients may have lymphoproliferation, autoimmunity, inflammation, allergy and malignancy. Recently, three groups have independently reported patients having mutations in STK4 gene that cause a novel autosomal recessive (AR) CID. We describe here two siblings with a novel STK4 mutation identified during the evaluation of a group of patients with features highly overlapping with those of DOCK-8 deficiency, a form of AR hyperimmunoglobulin E syndrome. The patients' clinical features include autoimmune cytopenias, viral skin (molluscum contagiosum and perioral herpetic infection) and bacterial infections, mild onychomycosis, mild atopic and seborrheic dermatitis, lymphopenia (particularly CD4 lymphopenia), and intermittent mild neutropenia. Determination of the underlying defect and reporting the patients are required for the description of the phenotypic spectrum of each immunodeficiency.


Asunto(s)
Enfermedades Autoinmunes/genética , Síndrome de Job/genética , Linfopenia/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Hermanos , Enfermedades Autoinmunes/diagnóstico , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Síndrome de Job/diagnóstico , Síndrome de Job/terapia , Linfopenia/diagnóstico , Linfopenia/terapia , Masculino , Linaje , Proteínas Serina-Treonina Quinasas/deficiencia
6.
Immunol Res ; 70(1): 56-66, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34622368

RESUMEN

In the diagnosis of primary immunodeficiencies which are heterogeneous groups of genetic disorders, next-generation sequencing strategies take an important place. Protein expression analyses and some functional studies which are fundamental to determine the pathogenicity of the mutation are also performed to accelerate the diagnosis of PIDs before sequencing. However, protein expressions and functions do not always reflect the genetic and clinical background of the disease even the existence of a pathogenic variant or vice versa. In this study, it was aimed to understand genotype-proteophenotype-clinicophenotype correlation by investigating the effect of mutation types on protein expression, function, and clinical severity in X-linked, autosomal dominant, and autosomal recessive forms of PIDs. It was searched in PubMed and Web of Science without any restrictions on study design and publication time. Totally, 1178 patients with PIDs who have 553 different mutations were investigated from 174 eligible full-text articles. For all mutations, the effect of mutation type on protein expressions and protein functions was analyzed. Furthermore, the most frequent missense and nonsense mutations that were identified in patients with PIDs were evaluated to determine the genotype-clinicophenotype correlation. Protein expressions and functions were changed depending on the mutation type and the affected domain. A significant relationship was observed between protein expression level and clinical severity among all investigated patients. There was also a positive correlation between clinical severity and the affected domains. Mutation types and affected domains should be carefully evaluated with respect to protein expression levels and functional changes during the evaluation of clinico-phenotype.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Genotipo , Humanos , Mutación/genética , Fenotipo
7.
J Allergy Clin Immunol Pract ; 9(10): 3752-3766.e4, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34146746

RESUMEN

BACKGROUND: Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency. OBJECTIVE: We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy. METHODS: In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls. RESULTS: In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics. CONCLUSIONS: The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfopenia , Herpesvirus Humano 4 , Humanos , Péptidos y Proteínas de Señalización Intracelular , Linfopenia/diagnóstico , Proteínas Serina-Treonina Quinasas , Serina , Treonina
8.
J Crit Care ; 35: 185-90, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27481757

RESUMEN

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled inflammation and has common clinical and laboratory features with sepsis. The aim of this study was to investigate patients treated with severe sepsis who had bicytopenia for the presence of HLH. MATERIALS AND METHODS: Patients with severe sepsis who were non-responsive to treatment and developed at least bicytopenia were included. Peripheral blood samples were collected and stored for later evaluation for natural killer (NK) activity and soluble interleukin-2 receptor levels. Diagnostic criteria of HLH were retrospectively analyzed. RESULTS: Seventy-five of 382 patients (20%) were followed as severe sepsis and septic shock. Among them, 40 patients had bicytopenia. Twenty-six of 40 patients were excluded due to the presence of active solid or hematological malignancies. Three patients died before fulfillment of HLH criteria and one patient denied to give consent. All of the remaining 10 patients had at least five of the eight criteria according to criteria of the Histiocyte Society. Only one of 10 patients was diagnosed as HLH and received treatment during intensive care unit stay. None of the 10 patients survived. CONCLUSIONS: This study emphasizes to consider the possibility of HLH and the need of rapid assessment of patients with severe sepsis who had bicytopenia and were resistant to treatment in intensive care.


Asunto(s)
Linfohistiocitosis Hemofagocítica/diagnóstico , Sepsis/diagnóstico , Adulto , Anciano , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Humanos , Inflamación/patología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Células Asesinas Naturales/citología , Tiempo de Internación , Masculino , Persona de Mediana Edad , Receptores de Interleucina-2/sangre , Estudios Retrospectivos , Adulto Joven
9.
Oncol Lett ; 9(3): 1482-1488, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25663935

RESUMEN

Loss of Forkhead box P1 (FOXP1) protein expression confers a poor prognosis in sporadic and familial breast cancer patients, and the FOXP1 gene maps to a tumor suppressor locus at chromosome 3p14. Although correlation studies have indicated that FOXP1 has a role in tumor suppression, determination of the regulatory mechanism of FOXP1 is required to establish its function in breast cancer. It has previously been identified that FOXP1 is regulated by estrogen in breast cancer and that treatment with bisphenol A is effective for regulating the transformation of the normal human breast epithelial cell line, MCF-10F. In addition, FOXO-regulated activation of FOXP1 inhibits the apoptosis of MCF-10F cells following tamoxifen and Akt inhibitor VIII administration. The present study indicates that FOXP1 regulation occurs via a PI3K/Akt/p70S6 kinase (p70S6K) signaling pathway. Following treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt, MCF7 and MDA-MB-231 breast cancer cells demonstrated decreased FOXP1 protein expression levels; this result was also observed in the small interfering (si)RNA silencing of Akt. By contrast, overexpression of Akt resulted in increased FOXP1 protein expression levels in the MDA-MB-231 cells compared with the control cell lysates. Furthermore, treatment with rapamycin, a specific inhibitor of the mammalian target of rapamycin/p70S6K cascade, resulted in decreased FOXP1 expression in the MCF7 cells, but not in the MDA-MB-231 cells, which were resistant to rapamycin-induced inhibition. In addition, silencing of p70S6K using siRNA produced a marked decrease in FOXP1 expression. These data indicate that FOXP1 protein expression is regulated by a PI3K/Akt/p70S6K signaling cascade in breast cancer.

10.
Mol Med Rep ; 12(1): 595-600, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25760020

RESUMEN

Nuclear factor-κB (NF-κB) is involved in the regulation of inflammation­associated genes. NF-κB forms dimers which bind with sequences referred to as NF-κB sites (9-11 bp). A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 (ADAMTS9) is a type of proteoglycanase, which proteolytically cleaves versican and aggrecan. ADAMTS9 is a cytokine-inducible gene that contains binding sites for NF-κB within its promoter region. Interleukin-1ß (IL-1ß) affects cartilage metabolism and is involved in the NF-κB pathway. It is therefore hypothesized that NF-κB binding with ADAMTS9 promoters may activate IL-1ß, thereby promoting chondrocytic cell growth. In the present study, the OUMS-27 chondrocytic human chondrosarcoma cell line was treated with IL-1ß with or without inhibitors of NF-κB signaling pathways. Chromatin immunoprecipitation (ChIP) and electromobility shift assays (EMSA) were conducted order to analyze the binding of NF-κB with the ADAMTS9 promoter region. NF-κB-p65 subunit phosphorylation was promoted in IL-1ß-treated cells, which were not treated with inhibitors of NF-κB signaling pathways. By contrast, NF-κB-p65 subunit phosphorylation was inhibited in cells that had been treated with BAY-117085, an NF-κB pathway inhibitor. ChIP and EMSA assays demonstrated that, following treatment with IL-1ß, NF-κB­p65 bound to elements located at -1177 and -1335 in the ADAMTS9 promoter region, in contrast to the untreated samples. The results of the present study suggested that NF-κB may be involved in IL-1ß-induced activation of ADAMTS9 in human chondrocytes.


Asunto(s)
Proteínas ADAM/metabolismo , Neoplasias Óseas/genética , Condrosarcoma/genética , Interleucina-1beta/metabolismo , Factor de Transcripción ReIA/metabolismo , Proteínas ADAM/genética , Proteína ADAMTS9 , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Condrocitos/metabolismo , Condrocitos/patología , Condrosarcoma/metabolismo , Condrosarcoma/patología , Humanos , Interleucina-1beta/administración & dosificación , Nitrilos/administración & dosificación , Fosforilación , Regiones Promotoras Genéticas , Unión Proteica , Sulfonas/administración & dosificación , Factor de Transcripción ReIA/genética
11.
Oncol Lett ; 6(3): 807-810, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24137415

RESUMEN

Radiotherapy serves as adjunctive treatment to chemotherapy and surgical resection of colorectal cancer. However, the cellular response to irradiation varies depending on the expression of tumor suppressor p53, which plays a significant role in the regulation of cell cycle arrest, apoptosis and telomerase activity in various cancers. The present study aimed to investigate cell cycle arrest, apoptosis and telomerase activity with respect to p53 expression in p53 wild-type (+/+) and deficient (-/-) HCT116 colon cancer cell lines following 5 Gy γ-irradiation. Cell cycle arrest and apoptosis were evaluated using flow cytometry. The telomerase activity was measured using a TRAP (telomerase repeat amplification protocol) assay. Following treatment with irradiation, G1/S cell cycle arrest occurred in the p53+/+ cells, whereas the p53-/- cells accumulated in the G2 phase. No differences were observed in the apoptotic ratios between the two cell lines following irradiation. Decreased telomerase activity was observed in the p53+/+ cells, whereas telomerase activity was increased in the p53-/- cells. The results showed that while telomerase activity and G1 cell cycle arrest were regulated depending on the p53 status, G2 arrest and the apoptotic response were promoted via a p53-independent pathway.

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