RESUMO
The Janus family of tyrosine kinases (JAK) plays an essential role in development and in coupling cytokine receptors to downstream intracellular signaling events. A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 fusion protein includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain. TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.
Assuntos
Leucemia-Linfoma de Células T do Adulto/metabolismo , Proteínas do Leite , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sequência de Aminoácidos , Animais , Sequência de Bases , Biopolímeros , Divisão Celular , Linhagem Celular , Pré-Escolar , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , Humanos , Interleucina-3/fisiologia , Janus Quinase 2 , Leucemia-Linfoma de Células T do Adulto/genética , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/genética , Fosforilação , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-ets , Fator de Transcrição STAT5 , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1alpha-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein. Functional studies show that TEL-ARNT interacts with HIF1alpha and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1alpha/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34+ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.
Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/fisiologia , Hematopoese/genética , Oxigênio/sangue , Proteínas Proto-Oncogênicas c-ets/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Proteínas Repressoras/fisiologia , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Diferenciação Celular/genética , Linhagem Celular , Células HeLa , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Repressoras/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Most of the translocations affecting the chromosome band 11q23, frequently seen in human acute leukemias, involve a restricted area of the HRX gene. We have characterized two t(1;11)(p32;q11) translocations which fuse the HRX gene to a novel gene, AF-1p on chromosome 1p32, in two myeloid leukemias. The der (11) chromosome expresses the 1368 N-terminal amino acids of HRX, including the AT-hook, snRNP and methyltransferase similarities, fused to almost all the AF-1p product. The predicted wild type AF-1p product is a 98 kDa acidic protein which does not exhibit similarity to the AF-4, AF-9 and ENL gene products. It is highly similar to the murine eps 15 gene product, which encodes a cytoplasmic phosphoprotein. Our data indicate that AF-1p defines another class of genes fused to HRX in 11q23 abnormalities.
Assuntos
Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Leucemia Monocítica Aguda/genética , Leucemia Mieloide/genética , Fosfoproteínas , Proto-Oncogenes , Fatores de Transcrição , Translocação Genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Sequência de Aminoácidos , Sequência de Bases , Northern Blotting , Pré-Escolar , Clonagem Molecular , Sequência Consenso , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Dedos de ZincoRESUMO
We have recently described a t(8;14)(q24;q11) translocation which appeared secondarily in a non-established acute T-cell leukaemia and involved the 3' region of c-myc proto-oncogene and the alpha chain of the T-cell receptor gene (TcR-alpha). In order to elucidate the mechanism of the translocation, we have isolated breakpoint regions from normal and recombinant chromosomes. Our results show that the translocation occurred at the 3' end of a V alpha segment in the proximity of recombination signal sequences (5'-heptamer-23bp spacer-nonamer-3'). Interestingly, an inverted heptamer internal to the V alpha segment was found at two nucleotides 5' of the break. Nucleotide sequence analysis also revealed the presence of homologous signal sequences on chromosome 8, suggesting that the recombination enzymatic system played an important role in the generation of the translocation. This hypothesis is supported by the addition of N nucleotides and the loss of only three nucleotides during the rejoining process. These data established the involvement of a V alpha segment and its recombination signals in the mechanisms of t(8;14) translocations in T-cell leukaemias.
Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Leucemia/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Antígenos de Linfócitos T/genética , Translocação Genética , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA de Neoplasias/genética , Genes , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc , Receptores de Antígenos de Linfócitos T alfa-beta , Recombinação Genética , Linfócitos TRESUMO
Analysis of several cases of t(1:14)(p32;q11) translocation present in 3% of T-cell acute leukemias (T-ALL) has revealed the tal-1 gene. This gene encodes a helix-loop-helix protein. It has been found to be expressed in normal bone marrow and in leukemic T-cell and erythroleukemia cell lines, but not in normal T cells. Recently, a site-specific deletion, tald, renamed tald1 in this paper, has been detected in a high proportion of pediatric T-ALL, which arose by a site-specific DNA recombination between tal-1 and a new locus termed SIL. In this study we searched for structural rearrangements within tal-1 in a panel of 134 non-selected leukemic patients (including 66 with T-ALL). Only 6% of patients with T-ALL harbored the tald1 deletion. A second specific deletion termed tald2 was observed in another 6% of T-ALL patients; it involves another site within tal-1 plus the same site as tald1 in the SIL locus. Similarly to tald1 deletion, tald2 junctions harbor structural characteristics that are reminiscent of aberrant recombinase activity. Moreover, we report a detailed analysis of the tal-1 gene structure. Transcription analysis and in vitro translation data are consistent with the differential expression of several TAL-1 protein species containing the HLH motif but differing in their amino terminus. Taken together, our data indicate that t(1;14) translocations and both tald deletions disrupt the 5' part of the tal-1 gene, placing its entire coding sequences under the control of the regulatory elements of the TCR-delta gene or the SIL gene, both of which are normally expressed in T-cell lineage.
Assuntos
Deleção Cromossômica , Leucemia-Linfoma de Células T do Adulto/genética , Translocação Genética/genética , Sequência de Aminoácidos , Sequência de Bases , Medula Óssea/metabolismo , Medula Óssea/patologia , Medula Óssea/ultraestrutura , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 14 , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Genes Reguladores/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Dados de Sequência Molecular , Estrutura Molecular , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transcrição Gênica/genética , Células Tumorais CultivadasRESUMO
The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.
Assuntos
Proteínas de Transporte/biossíntese , Citocinas/biossíntese , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Repressoras/biossíntese , Animais , Linfócitos B/metabolismo , Linhagem Celular Transformada , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Janus Quinase 2 , Camundongos , Complexos Multienzimáticos/metabolismo , Complexo de Endopeptidases do Proteassoma , Ligação Proteica , Receptores de Interferon/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina , Ubiquitinas/metabolismo , Receptor de Interferon gamaRESUMO
The human TEL gene is involved in several 12p13 chromosomal abnormalities present in various human hematological malignancies, the most frequent being the t(12;21)(p13;q22), specific for childhood acute lymphoblastic leukemia. The predicted product of TEL harbours an amino acid region similar to the ETS DNA binding domain. We now report the isolation of the murine TEL cDNA and the characterization of the human TEL proteins. Human and murine TEL proteins are particularly homologous within their aminoterminal regions and their ETS domains. TEL proteins are nuclear and display specific DNA binding activity toward classical ETS binding sites. In addition, we show that TEL mRNAs initiate translation at either of the two first inframe ATGs (codon 1 and 43) to encode 50 kDa and 57 kDa TEL proteins. In vivo, each of these primary translational products is modified by multiple phosphorylation events.
Assuntos
DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Animais , Sequência de Bases , Western Blotting , Células COS , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Clonagem Molecular , DNA/metabolismo , DNA Complementar/isolamento & purificação , Proteínas de Ligação a DNA/isolamento & purificação , Humanos , Hibridização in Situ Fluorescente , Leucemia de Células B/genética , Camundongos , Dados de Sequência Molecular , Proteínas Nucleares/isolamento & purificação , Fosfoproteínas/isolamento & purificação , Fosforilação , Proteínas Proto-Oncogênicas c-ets , RNA Mensageiro/isolamento & purificação , Fatores de Transcrição/isolamento & purificação , Translocação Genética , Células Tumorais Cultivadas , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
The TEL/ETV6 gene is located at 12p13 and is frequently involved in chromosomal translocations in human malignancies usually resulting in the expression of fusion proteins between the amino terminal part of TEL, and either unrelated transcription factors or protein tyrosine kinases. We report here a novel gene named TELB which is located on human chromosomal band 6p21 and encodes a protein highly related to TEL. TELB is widely expressed in different tissues and, similarly to TEL encodes a sequence-specific transcriptional repressor.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila , Genes , Leucemia/genética , Proteínas Proto-Oncogênicas , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Linfoma de Burkitt/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 6/ultraestrutura , Subunidade alfa 2 de Fator de Ligação ao Core , DNA Complementar/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/biossíntese , Drosophila melanogaster/genética , Éxons/genética , Etiquetas de Sequências Expressas , Proteínas do Olho/genética , Regulação Leucêmica da Expressão Gênica , Células HeLa , Humanos , Dados de Sequência Molecular , Família Multigênica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Fatores de Transcrição/biossíntese , Transcrição Gênica , Transfecção , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT-PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Proteínas de Ligação a DNA/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Fatores de Transcrição/metabolismo , Adulto , Animais , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Células HL-60 , Células HeLa , Humanos , Isomerismo , Leucemia Mielomonocítica Aguda/patologia , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-ets , Coelhos , Frações Subcelulares , Translocação Genética , Células Tumorais Cultivadas , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
The HRX gene has recently been shown to be involved in most of the chromosomal abnormalities of band 11q23 frequently present in human hematological malignancies. Rearrangements are strikingly diverse, but most affect a restricted area of the HRX gene and lead to gene fusion between HRX and a gene located on the partner chromosome. Another kind of HRX alteration seen in human acute leukemia is a partial duplication of the NH2 part of the HRX locus. We have characterized two cases of partial HRX duplication in acute leukemias bearing trisomy 11 as the sole chromosomal abnormality. In one patient analyzed at the genomic level, an Alu repeat was involved within exon 6 but not within intron 1. Splicing of exon 6 to exon 2 was observed in this patient while splicing of exon 8 to exon 2 was observed in the other. Our data indicated that HRX duplication is highly similar to the translocation affecting the HRX locus both in the restricted diversity of the fusion points and the involvement of Alu repeats within the breakpoint cluster region (exon 5 to 10).
Assuntos
Anemia Refratária com Excesso de Blastos/genética , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 11/genética , Leucemia Mieloide/genética , Leucemia Prolinfocítica/genética , Trissomia , Doença Aguda , Idoso , Sequência de Bases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Transcrição GênicaRESUMO
The TEL gene is involved in several chromosomal abnormalities of human hematopoietic malignancies. The chromosome 12 breakpoints frequently lie within the fifth intron of the gene, particularly in the most frequent translocation involving TEL, the t(12;21)(p13;q22). In order to search for a peculiar mechanism involved in the genesis of these translocations, we have established the sequence of two t(12;21) and a t(9;12)(q24;p13) breakpoints. Our data do not reveal the involvement of VDJ recombinase activity or Alu sequences but favor the occurrence of staggered breaks and DNA repair activity in the genesis of these translocations.
Assuntos
Linfoma de Burkitt/genética , Quebra Cromossômica/genética , Cromossomos Humanos Par 12/genética , Proteínas de Ligação a DNA/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Translocação Genética/genética , Alelos , Elementos Alu/genética , Sequência de Bases , Criança , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA Nucleotidiltransferases/metabolismo , Reparo do DNA/genética , Éxons/genética , Humanos , Íntrons/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Mapeamento Físico do Cromossomo , Proteínas Proto-Oncogênicas c-ets , Recidiva , VDJ Recombinases , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
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/genéticaRESUMO
Toyocamycin (TMC), an adenosine analog has been previously reported to inhibit both number and infectivity of retrovirus particles released by chronically infected cells (Bonar et al., 1970; Riman, 1971; Mauchauffé et al., 1979). We have previously shown that loss of infectivity could result from the incorporation of TMC in place of adenosine in the genomic 35S RNA (Larsen et al., 1979). This phenomenon is likely to impair the structure of the viral genome in such a way that reverse transcriptase cannot properly copy the template. Another consequence of the Toyocamycin action on the retrovirus particles released by analog-treated cells was their reduced content in envelope glycoprotein or gp70 (Mathieu - Mahul et al., 1979). In order to find the origin of this defect, which could also explain the loss of infectivity, viral polypeptides present in the cytoplasm of Toyocamycin-treated cells were analyzed by immunoprecipitation with specific antisera. The results indicated a diminution of the biosynthesis of the envelope glycoprotein and other GAG gene-related polypeptides. However, the gpr85env precursor was normally synthesized and processed into its final products (gp70 + p15E), which accumulated in the cells. These result make it likely that Toyocamycin has no specific effect on the virus replicative process in chronically infected cells but acts by deteriorating cellular functions, which are necessary to virus assembly. Indeed, it was found that a membrane fraction corresponding to smooth endoplasmic reticulum and Golgi apparatus was severely reduced if not totally suppressed in TMC-treated cells.
Assuntos
Vírus da Leucemia Murina de Friend/metabolismo , Glicoproteínas/biossíntese , Ribonucleosídeos/farmacologia , Toiocamicina/farmacologia , Proteínas Virais/biossíntese , Animais , Linhagem Celular , Membranas/metabolismo , CamundongosRESUMO
This paper summarizes the results of a study on human breast cancers performed mainly at the Centre René Huguenin in collaboration with other American and French groups, and supported in part by a Grant from the Association pour la Recherche sur le Cancer (ARC) Villejuif. During this work, the following conclusions emerged: c-myc proto-oncogene amplification is a common alteration in ductal invasive tumors, more frequently found in recurrent and metastatic tumors, suggesting a role for c-myc in tumor progression. However, in the current state of our study, it does not appear to be linked to prognosis; parts of the short arm of chromosome 11 are deleted in 20% of tumors resulting in hemizygosity for several genes (c-ha-ras, beta globin, pTH, calcitonin, catalase). These deletions seem to be linked with aggressiveness of tumors; a restriction fragment length polymorphism (RFLP) study of c-ha-ras has shown a significant association of the frequency of rare ha-ras alleles in cancer patients compared to that of normal individuals. Although this result is currently a matter of controversy, further studies must be independently repeated to be conclusive; -- another RFLP was found in c-mos proto-oncogene, which is detected only in patients with breast cancers or other types of tumors. The molecular basis for this RFLP has been elucidated. The significance of this association is unknown.
Assuntos
Neoplasias da Mama/genética , Proto-Oncogenes , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Deleção Cromossômica , Feminino , Amplificação de Genes , Genes ras , Humanos , Polimorfismo de Fragmento de Restrição , Prognóstico , Proto-Oncogene Mas , Fatores de RiscoAssuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Leucemia Linfoide/genética , Translocação Genética , Sequência de Bases , Feminino , Antígenos HLA/genética , Humanos , Masculino , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T/genética , Células Tumorais CultivadasAssuntos
Antibióticos Antineoplásicos/farmacologia , Vírus da Leucemia Murina de Friend/metabolismo , RNA Viral/metabolismo , Toiocamicina/farmacologia , Citoplasma/metabolismo , DNA Viral , Vírus da Leucemia Murina de Friend/efeitos dos fármacos , Hibridização de Ácido Nucleico , RNA/metabolismo , Toiocamicina/metabolismoAssuntos
Monofosfato de Adenosina , Polinucleotídeos , RNA/isolamento & purificação , Animais , Sequência de Bases , Linhagem Celular , Celulose , Cromatografia de Afinidade , Gammaretrovirus , Hidrólise , Radioisótopos de Fósforo , Polinucleotídeos/síntese química , Polirribossomos , RNA/análise , RNA Mensageiro/isolamento & purificação , RNA Ribossômico , Ratos , Ribonucleases , UltracentrifugaçãoRESUMO
Toyocamycin (TMC), an adenosine analog, impairs qualitatively and quantitatively virus production in a cellular system chronically infected by Friend Virus. Viral particles released by cell cultures treated with 0.2 microgram/ml of the drug have lost most of their glycoprotein (gp 70) content. This phenomenon is likely to modify the viral envelope and could explain the loss of infectivity of the virus.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Retroviridae/efeitos dos fármacos , Toiocamicina/farmacologia , Animais , Glucosamina/metabolismo , Glicoproteínas/metabolismo , Camundongos , Peptídeos/metabolismo , Retroviridae/metabolismo , Retroviridae/ultraestrutura , Proteínas Virais/metabolismoRESUMO
The presence of a rearrangement of the proto-oncogene c-myc was investigated in the DNA of fresh cells isolated from the blood of two patients with Burkitt's leukemia (L3), and from the node biopsy of a patient with Burkitt's lymphoma. Both samples from the L3 leukemia patients had the characteristic t(8;14) translocation, while the lymphoma specimen presented no abnormality of chromosome 8. Only one of the leukemic DNA's presented a rearranged c-myc pattern, with the breakpoint region located between the first and the second exon. The c-myc pattern of the two other patients appeared normal. The finding of a rearranged c-myc oncogene in fresh cells from a Burkitt's leukemia is direct evidence for the implication of c-myc in the disease whereas most of the rearrangements previously described have been found in cell lines established in culture.
Assuntos
Leucemia Linfoide/genética , Translocação Genética , Sequência de Bases , Linfoma de Burkitt/genética , Cromossomos Humanos 6-12 e X , DNA/genética , Enzimas de Restrição do DNA , Humanos , Hibridização de Ácido Nucleico , Proto-Oncogene Mas , Proto-OncogenesRESUMO
Production of Friend virus by chronically infected cells (Friend-Eveline cell line) is depressed by Toyocamycin, an adenosine analogue, at doses which stop cellular growth. The infectivity and the endogenous reverse transcriptase activity of the virions are diminished. These effects are likely to be due to the incorporation of Toyocamycin into the 70S RNA.