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1.
Leukemia ; 15(10): 1495-504, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11587205

RESUMO

FISH identified a cryptic t(5;14)(q35;q32) in T acute lymphoblastic leukemia (ALL), whereas it was not observed in B ALL samples. This translocation is present in five out of 23 (22%) children and adolescents with T ALL tested. RanBP17, a gene coding for a member of the importin beta protein family, and Hox11Like2, an orphan homeobox gene were mapped close to the chromosome 5 breakpoints and CTIP2, which is highly expressed during normal T cell differentiation, was localized in the vicinity of the chromosome 14 breakpoints. The Hox11L2 gene was found to be transcriptionally activated as a result of the translocation, probably under the influence of CTIP2 transcriptional regulation elements. These data establish the t(5;14)(q35;q32) as a major abnormality, and Hox11 family member activation as an important pathway in T ALL leukemogenesis.


Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 5 , Proteínas de Homeodomínio/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Oncogênicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Sequência de Aminoácidos , Estudos de Casos e Controles , Transformação Celular Neoplásica , Criança , Pré-Escolar , Quebra Cromossômica , Análise Citogenética , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/etiologia , Masculino , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Proteínas Proto-Oncogênicas , Alinhamento de Sequência , Proteína ran de Ligação ao GTP/genética
2.
Proc Natl Acad Sci U S A ; 96(14): 8070-3, 1999 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-10393949

RESUMO

We have previously described biological model systems for studying tumor suppression in which, by using H-1 parvovirus as a selective agent, cells with a strongly suppressed malignant phenotype (KS or US) were derived from malignant cell lines (K562 or U937). By using cDNA display on the K562/KS cells, 15 cDNAs were now isolated, corresponding to genes differentially regulated in tumor suppression. Of these, TSAP9 corresponds to a TCP-1 chaperonin, TSAP13 to a regulatory proteasome subunit, and TSAP21 to syntaxin 11, a vesicular trafficking molecule. The 15 cDNAs were used as a molecular fingerprint in different tumor-suppression models. We found that a similar pattern of differential regulation is shared by activation of p53, p21(Waf1), and the human homologue of Drosophila seven in absentia, SIAH-1. Because SIAH-1 is differentially expressed in the various models, we characterized it at the protein and functional levels. The 32-kDa, mainly nuclear protein encoded by SIAH-1, can induce apoptosis and promote tumor suppression. These results suggest the existence of a common mechanism of tumor suppression and apoptosis shared by p53, p21(Waf1), and SIAH-1 and involving regulation of the cellular machinery responsible for protein folding, unfolding, and trafficking.


Assuntos
Ciclinas/genética , Genes p53 , Neoplasias/genética , Proteínas Nucleares/genética , Dobramento de Proteína , Animais , Apoptose , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Drosophila/genética , Humanos , Células K562 , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Parvovirus/genética , Transfecção , Proteína Supressora de Tumor p53/metabolismo , Células U937 , Ubiquitina-Proteína Ligases
4.
Proc Natl Acad Sci U S A ; 93(17): 9039-42, 1996 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-8799150

RESUMO

Developmentally regulated genes in Drosophila, which are conserved through evolution, are potential candidates for key functions in biological processes such as cell cycle, programmed cell death, and cancer. We report cloning and characterization of the human homologue of the Drosophila seven in absentia gene (HUMSIAH), which codes for a 282 amino acids putative zinc finger protein. HUMSIAH is localized on human chromosome 16q12-q13. This gene is activated during the physiological program of cell death in the intestinal epithelium. Moreover, human cancer-derived cells selected for suppression of their tumorigenic phenotype exhibit constitutively elevated levels of HUMSIAH mRNA. A similar pattern of expression is also displayed by the p21waf1. These results suggest that mammalian seven in absentia gene, which is a target for activation by p53, may play a role in apoptosis and tumor suppression.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica , Genes Supressores de Tumor , Proteínas Nucleares/genética , Proteínas/genética , Homologia de Sequência de Aminoácidos , Sequência de Aminoácidos , Animais , Cromossomos Humanos Par 16 , DNA Complementar/genética , Biblioteca Gênica , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Ubiquitina-Proteína Ligases , Dedos de Zinco
5.
Proc Natl Acad Sci U S A ; 93(9): 3953-7, 1996 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-8632996

RESUMO

We report the isolation of 10 differentially expressed cDNAs in the process of apoptosis induced by the p53 tamor suppressor. As a global analytical method, we performed a differential display of mRNA between mouse M1 myeloid leukemia cells and derived clone LTR6 cells, which contain a stably transfected temperature-sensitive mutant of p53. At 32 degrees C wild-type p53 function is activated in LTR6 cells, resulting in programmed cell death. Eight genes are activated (TSAP; tumor suppressor activated pathway), and two are inhibited (TSIP, tumor suppressor inhibited pathway) in their expression. None of the 10 sequences has hitherto been recognized as part of the p53 signaling pathway. Three TSAPs are homologous to known genes. TSAP1 corresponds to phospholipase C beta 4. TSAP2 has a conserved domain homologous to a multiple endocrine neoplasia I (ZFM1) candidate gene. TSAP3 is the mouse homologue of the Drosophila seven in absentia gene. These data provide novel molecules involved in the pathway of wild-type p53 activation. They establish a functional link between a homologue of a conserved developmental Drosophila gene and signal transduction in tumor suppression leading to programmed cell death.


Assuntos
Apoptose , DNA Complementar/metabolismo , Drosophila/genética , Genes p53 , Proteínas Nucleares/genética , Animais , Sequência de Bases , Células Clonais , Primers do DNA , DNA Complementar/isolamento & purificação , Genes de Insetos , Leucemia Experimental , Leucemia Mieloide Aguda , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Mensageiro , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases , Vertebrados
6.
Am J Hum Genet ; 56(6): 1417-30, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7762565

RESUMO

A gene for a recessive form of limb-girdle muscular dystrophy (LGMD2A) has been localized to chromosome 15. A physical map of the 7-cM candidate 15q15.1-q21.1 region has been constructed by means of a 10-12-Mb continuum of overlapping YAC clones. New microsatellite markers developed from these YACs were genotyped on large, consanguineous LGMD2A pedigrees from different origins. The identification of recombination events in these families allowed the restriction of the LGMD2A region to an estimated 1-cM interval, equivalent to approximately 3-4 Mb. Linkage disequilibrium data on genetic isolates from the island of Réunion and from the Amish community suggest a preferential location of the LGMD2A gene in the proximal part of this region. Analysis of the interrelated pedigrees from Réunion revealed the existence of at least six different carrier haplotypes. This allelic heterogeneity is incompatible with the presumed existence of a founder effect and suggests that multiple LGMD2A mutations may segregate in this population.


Assuntos
Cromossomos Humanos Par 15/genética , Distrofias Musculares/genética , Sequência de Bases , Mapeamento Cromossômico , Consanguinidade , DNA Satélite , Feminino , Marcadores Genéticos , Genótipo , Haplótipos , Heterozigoto , Homozigoto , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Distrofias Musculares/epidemiologia , Linhagem , Polimorfismo Genético , Recombinação Genética , Reunião/epidemiologia
7.
Cell ; 81(1): 27-40, 1995 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-7720071

RESUMO

Limb-girdle muscular dystrophies (LGMDs) are a group of inherited diseases whose genetic etiology has yet to be elucidated. The autosomal recessive forms (LGMD2) constitute a genetically heterogeneous group with LGMD2A mapping to chromosome 15q15.1-q21.1. The gene encoding the muscle-specific calcium-activated neutral protease 3 (CANP3) large subunit is located in this region. This cysteine protease belongs to the family of intracellular calpains. Fifteen nonsense, splice site, frameshift, or missense calpain mutations cosegregate with the disease in LGMD2A families, six of which were found within La Réunion island patients. A digenic inheritance model is proposed to account for the unexpected presence of multiple independent mutations in this small inbred population. Finally, these results demonstrate an enzymatic rather than a structural protein defect causing a muscular dystrophy, a defect that may have regulatory consequences, perhaps in signal transduction.


Assuntos
Calpaína/genética , Distrofias Musculares/genética , Mutação/genética , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 15 , DNA/sangue , Análise Mutacional de DNA , Éxons/genética , Expressão Gênica , Testes Genéticos , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Distrofias Musculares/enzimologia , Distrofias Musculares/etnologia , Ácidos Nucleicos Heteroduplexes , Reação em Cadeia da Polimerase/métodos , Mapeamento por Restrição , Alinhamento de Sequência
8.
Hum Mol Genet ; 4(4): 717-25, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7633422

RESUMO

Previous genetic and physical studies of LGMD2A, an autosomal recessive form of limb-girdle muscular dystrophy, have led to the establishment of a 10-12 Mb YAC contig encompassing the morbid locus. In order to progress toward the identification of the gene involved in LGMD2A, a primary transcription map of this genomic region was generated. The direct cDNA selection strategy was used with three YACs covering the candidate region and two different muscle cDNA libraries. Seventeen transcription units were identified among 171 cDNA fragments analysed. Five sequences corresponded to known genes, and twelve to new ones. They were characterized for their sequences, physical positions within the YAC contig, and expression patterns. Among those specifically transcribed in muscle, the calpain gene is a good positional and functional candidate for LGMD2A.


Assuntos
Cromossomos Humanos Par 15 , Distrofias Musculares/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Clonagem Molecular , DNA Complementar , Humanos , Dados de Sequência Molecular , Músculos/metabolismo , Homologia de Sequência de Aminoácidos , Transcrição Gênica
9.
Genomics ; 23(3): 619-27, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7851890

RESUMO

One hundred forty-nine chromosome 15 loci were mapped by PCR with respect to chromosome breakpoints in three somatic cell hybrids retaining total or part of chromosome 15 and to a 10-Mb YAC contig. This chromosome was subdivided into 5 regions, yielding an average resolution of more than 1 sequence tagged site per megabase. The mapped loci included 18 genes, 60 cDNA-derived sequence tagged sites, and 69 microsatellites. In addition, the amount of chromosome 15 retained in line A15.1 has been defined. This work represents the first attempt at an integration of the human physical, expression, and genetic maps of chromosome 15.


Assuntos
Cromossomos Humanos Par 15 , Hominidae/genética , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Cricetinae , Cricetulus , Primers do DNA , Bases de Dados Factuais , Expressão Gênica , Marcadores Genéticos , Humanos , Células Híbridas , Camundongos , Dados de Sequência Molecular , Distribuição de Poisson , Reação em Cadeia da Polimerase/métodos , Polimorfismo Genético , Homologia de Sequência de Aminoácidos
10.
Hum Mol Genet ; 3(2): 285-93, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8004096

RESUMO

A gene responsible for an autosomal recessive form of limb girdle muscular dystrophy (LGMD2, MIM number 253600) has been localized on chromosome 15. After genotyping additional markers of this chromosome, two were found to flank the disease locus within an interval that was assessed as 7 centiMorgans. The screening of the CEPH YAC libraries with the corresponding probes allowed the isolation of YACs which were used in fluorescence in situ hybridization to define the LGMD2 cytogenetic interval as 15q15.1-15q21.1. Four different approaches were pursued for the establishment of the physical map of this area which allowed the assembly of an uninterrupted YAC contig spanning an estimated 10-12 megabases, with an average STS resolution of 140 kb or for the 25 polymorphic microsatellites on this map, of 400 kb. Twelve genes and 25 genetic markers were positioned in this contig, which is constituted of a minimum of 10 clones.


Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 15 , Genes Recessivos , Distrofias Musculares/genética , Passeio de Cromossomo , Cromossomos Artificiais de Levedura , Marcadores Genéticos , Genótipo , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase , Sitios de Sequências Rotuladas
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