Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
EMBO J ; 39(17): e104337, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32677087

RESUMEN

Integration of transposable elements into the genome is mutagenic. Mechanisms targeting integrations into relatively safe locations, hence minimizing deleterious consequences for cell fitness, have emerged during evolution. In budding yeast, integration of the Ty1 LTR retrotransposon upstream of RNA polymerase III (Pol III)-transcribed genes requires interaction between Ty1 integrase (IN1) and AC40, a subunit common to Pol I and Pol III. Here, we identify the Ty1 targeting domain of IN1 that ensures (i) IN1 binding to Pol I and Pol III through AC40, (ii) IN1 genome-wide recruitment to Pol I- and Pol III-transcribed genes, and (iii) Ty1 integration only at Pol III-transcribed genes, while IN1 recruitment by AC40 is insufficient to target Ty1 integration into Pol I-transcribed genes. Swapping the targeting domains between Ty5 and Ty1 integrases causes Ty5 integration at Pol III-transcribed genes, indicating that the targeting domain of IN1 alone confers Ty1 integration site specificity.


Asunto(s)
Integrasas/metabolismo , ARN Polimerasa III/metabolismo , ARN Polimerasa I/metabolismo , ARN de Transferencia/genética , Retroelementos , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Integrasas/genética , ARN Polimerasa I/genética , ARN Polimerasa III/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
2.
Clin Neuropathol ; 35(3): 106-13, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26857864

RESUMEN

The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 children aged < 5 years, with initial DNMB treated according to the HIT-SKK protocol, were evaluated. A retrospective central radiological review, a pathological and immunohistochemical study, and array-CGH and sequencing of germline SUFU and PTCH1 genes were performed. 15 histologically reviewed cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immunoprofile. A 9q deletion was found in 6 cases, a MYCN-MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overallsurvival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.


Asunto(s)
Neoplasias Cerebelosas/patología , Meduloblastoma/genética , Meduloblastoma/patología , Biomarcadores de Tumor/análisis , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/mortalidad , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Estimación de Kaplan-Meier , Masculino , Meduloblastoma/mortalidad , Mutación , Estudios Retrospectivos
3.
Pediatr Blood Cancer ; 61(2): 383-6, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24115570

RESUMEN

Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB.


Asunto(s)
Proteína de Unión a CREB/genética , Neoplasias Cerebelosas/etiología , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Meduloblastoma/etiología , Síndrome de Rubinstein-Taybi/complicaciones , Neoplasias Cerebelosas/patología , Hibridación Genómica Comparativa , Proteínas Hedgehog/genética , Humanos , Lactante , Masculino , Meduloblastoma/patología , Pronóstico , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patología , Eliminación de Secuencia , Proteínas Wnt/genética
4.
Histopathology ; 61(3): 428-35, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22686875

RESUMEN

AIMS: Renal medullary carcinoma (RMC), a rare and highly aggressive tumour which occurs in patients with sickle-cell disease, shares many clinicopathological features with collecting duct carcinoma (CDC). The molecular mechanisms underlying RMC and CDC are mainly unknown, and there is ongoing debate about their status as distinct entities. Loss of expression of SMARCB1/INI1, a chromatin remodelling regulator and repressor of cyclin D1 transcription, has been reported recently in RMC. The aim of our study was to investigate if such loss of expression is specific for RMC. SMARCB1/INI1 genetic alterations and cyclin D1 expression were also studied. METHODS AND RESULTS: Using immunochemistry, neoplastic cells showed complete loss of SMARCB1/INI1 expression in all six cases of RMC but in only one of 22 cases of CDC. In two RMC cases investigated, comparative genomic hybridization demonstrated complete loss of one SMARCB1/INI1 allele, with no other genomic imbalances, and no mutations were found on the remaining allele. Cyclin D1 was expressed in all RMCs, suggesting that SMARCB1/INI1 inactivation may result in increased cyclin D1 transcription. CONCLUSIONS: The specific SMARCB1/INI1 inactivation observed in RMCs suggests that RMC and CDC are different entities.


Asunto(s)
Carcinoma Medular/genética , Carcinoma de Células Renales/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Neoplasias Renales/genética , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Medular/metabolismo , Carcinoma de Células Renales/metabolismo , Proteínas Cromosómicas no Histona/análisis , Proteínas Cromosómicas no Histona/biosíntesis , Hibridación Genómica Comparativa , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/biosíntesis , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Renales/metabolismo , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína SMARCB1 , Factores de Transcripción/análisis , Factores de Transcripción/biosíntesis
6.
Nat Commun ; 7: 10421, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26818002

RESUMEN

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.


Asunto(s)
Neoplasias Encefálicas/genética , Proteínas Cromosómicas no Histona/genética , Tumor Rabdoide/genética , Animales , Neoplasias Encefálicas/inducido químicamente , Neoplasias Encefálicas/metabolismo , Preescolar , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Masculino , Ratones , Tumor Rabdoide/inducido químicamente , Tumor Rabdoide/metabolismo , Proteína SMARCB1 , Tamoxifeno/toxicidad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
7.
Virchows Arch ; 463(6): 837-42, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24213312

RESUMEN

The present study describes a new case of EWSR1-negative undifferentiated sarcoma with CIC/DUX4 gene fusion. This case is similar to tumors described as primitive undifferentiated round cell sarcomas that occur mainly in the trunk and display an aggressive behavior. To our knowledge, this is the first report of such a tumor presenting locoregional lymph node metastasis. In view of previous studies that prove the existence of a particular variant of undifferentiated sarcoma with Ewing-like morphology and CIC/DUX-4 gene fusion, a search for this gene fusion in all undifferentiated round cell sarcomas should be considered if a conclusive diagnosis cannot be reached following other conventional studies. Although additional cases with more extensive follow-up studies are needed, we believe that EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion should be added to the list of new sarcoma variants with the possibility of lymph node metastasis.


Asunto(s)
Proteínas de Unión a Calmodulina/genética , Proteínas de Homeodominio/genética , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Metástasis Linfática/genética , Metástasis Linfática/patología , Masculino , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
8.
Cancer Genet ; 206(4): 124-9, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23578955

RESUMEN

As prognostic factors, MYC and MYCN amplifications are routinely assessed in medulloblastomas. Fluorescence in situ hybridization (FISH) is currently considered as the technique of reference. Recently, array comparative genomic hybridization (aCGH) has been developed as an alternative technique to evaluate genomic abnormalities in other tumor types; however, this technique has not been widely adopted as a replacement for FISH in medulloblastoma. In this study, 34 tumors were screened by both FISH and aCGH. In all cases showing amplification by FISH, aCGH also unambiguously revealed the abnormality. The aCGH technique was also performed on tumors showing no amplification by FISH, and the absence of amplification was confirmed in all cases. Interestingly, one tumor showed a subclonal MYC amplification by FISH. This subclonal amplification was observed in approximately 20% of tumor cells and was clearly evident on aCGH. In conclusion, our analysis confirms that aCGH is as safe as FISH for the detection of MYC/MYCN gene amplification. Given its cost efficiency in comparison to two FISH tests and the global genomic information additionally provided by an aCGH experiment, this reproducible technique can be safely retained as an alternative to FISH for routine investigation of medulloblastoma.


Asunto(s)
Hibridación Genómica Comparativa/métodos , Amplificación de Genes , Genes myc , Meduloblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Humanos , Hibridación Fluorescente in Situ , Proteína Proto-Oncogénica N-Myc , Estudios Prospectivos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA