RESUMO
Human neurofibromatosis type 1 is a dominant disease caused by the inheritance of a mutant allele of the NF1 gene. In order to study NF1 function, we have constructed a mouse strain carrying a germline mutation in the murine homologue. Heterozygous animals do not exhibit the classical symptoms of the human disease, but are highly predisposed to the formation of various tumour types, notably phaeochomocytoma, a tumour of the neural crest-derived adrenal medulla, and myeloid leukaemia, both of which occur with increased frequency in human NF1 patients. The wild-type Nf1 allele is lost in approximately half of the tumours from heterozygous animals. In addition, homozygosity for the Nf1 mutation leads to abnormal cardiac development and mid-gestational embryonic lethality.
Assuntos
Modelos Animais de Doenças , Morte Fetal/genética , Genes da Neurofibromatose 1 , Cardiopatias Congênitas/genética , Camundongos Mutantes/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias das Glândulas Suprarrenais/genética , Alelos , Animais , Sequência de Bases , Genes Letais , Genes Sintéticos , Predisposição Genética para Doença , Cardiopatias Congênitas/embriologia , Heterozigoto , Humanos , Leucemia Mieloide/genética , Camundongos , Camundongos Knockout , Camundongos Mutantes/embriologia , Dados de Sequência Molecular , Síndromes Neoplásicas Hereditárias/embriologia , Neurofibromatose 1/genética , Neurofibromina 1 , Fenótipo , Feocromocitoma/genética , Proteínas/genética , Proteínas/fisiologia , Especificidade da EspécieRESUMO
Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. Enzyme activity is undetectable in most normal cells and tissues, but present in immortal cells and cancer tissues. While expression of TERC, the RNA component of telomerase, is widespread, the restricted expression pattern of TERT, the telomerase catalytic subunit gene, is correlated with telomerase activity, and its ectopic expression in telomerase-negative cells is sufficient to reconstitute telomerase activity and extend cellular lifespan. We have used in situ hybridization to study TERT expression at the single-cell level in normal tissues and in various stages of tumour progression. In normal tissues, including some that are known to be telomerase-negative, TERT mRNA was present in specific subsets of cells thought to have long-term proliferative capacity. This included mitotically inactive breast lobular epithelium in addition to some actively regenerating cells such as the stratum basale of the skin. TERT expression appeared early during tumorigenesis in vivo, beginning with early pre-invasive changes in human breast and colon tissues and increasing gradually during progression, both in the amount of TERT mRNA present within individual cells and in the number of expressing cells within a neoplastic lesion. The physiological expression of TERT within normal epithelial cells that retain proliferative potential and its presence at the earliest stages of tumorigenesis have implications for the regulation of telomerase expression and for the identification of cells that may be targets for malignant transformation.
Assuntos
Transformação Celular Neoplásica/metabolismo , Lesões Pré-Cancerosas/genética , Biossíntese de Proteínas , Proteínas/genética , RNA não Traduzido , Telomerase/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Catálise , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA , Ativação Enzimática , Feminino , Expressão Gênica , Humanos , Hibridização In Situ , RNA/metabolismo , RNA Longo não Codificante , RNA Mensageiro/metabolismo , Células Tumorais CultivadasRESUMO
Research over the past two decades has defined a window of time in the early/mid G1 phase of the cell cycle during which mammalian cells are responsive to extracellular signals. Recent evidence indicates that this period ends with the phosphorylation of the retinoblastoma protein, enabling the cells to pass through the restriction point at the end of mid G1 phase and to commit to completing the remaining phases of the growth cycle.
Assuntos
Divisão Celular/fisiologia , Animais , Relógios Biológicos , Humanos , Fosforilação , Proteína do Retinoblastoma/metabolismo , Transdução de SinaisRESUMO
Senescence is now understood to be the final phenotypic state adopted by a cell in response to several distinct cell physiological processes, including proliferation, oncogene activation and oxygen free radical toxicity. The role of telomere maintenance in immortalization and the roles of p16(INK4A), p19(ARF), p53 and other genes in senescence are being further elucidated. Significant progress continues to be made in our understanding of cellular senescence and immortalization.
Assuntos
Senescência Celular/genética , Animais , Divisão Celular/genética , Regulação da Expressão Gênica , Genes p16/genética , Humanos , Camundongos , Oncogenes/genética , Estresse Oxidativo/genética , Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Telômero/genética , Telômero/metabolismo , Proteína Supressora de Tumor p14ARFRESUMO
Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that has a principal role in growth control through both its cytostatic effect on many different epithelial cell types and its ability to induce programmed cell death in a variety of other cell types. Here we have used a screen for proteins that interact physically with the cytoplasmic domain of the type II TGF-beta receptor to isolate the gene encoding Daxx - a protein associated with the Fas receptor that mediates activation of Jun amino-terminal kinase (JNK) and programmed cell death induced by Fas. The carboxy-terminal portion of Daxx functions as a dominant-negative inhibitor of TGF-beta-induced apoptosis in B-cell lymphomas, and antisense oligonucleotides to Daxx inhibit TGF-beta-induced apoptosis in mouse hepatocytes. Furthermore, Daxx is involved in mediating JNK activation by TGF-beta. Our findings associate Daxx directly with the TGF-beta apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-beta and the apoptotic machinery.
Assuntos
Apoptose/genética , Proteínas de Transporte/genética , Divisão Celular/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Nucleares , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Crescimento Transformador beta/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose/efeitos dos fármacos , Células COS/citologia , Células COS/efeitos dos fármacos , Células COS/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Compartimento Celular/efeitos dos fármacos , Compartimento Celular/genética , Divisão Celular/efeitos dos fármacos , Proteínas Correpressoras , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Proteína Quinase 8 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Chaperonas Moleculares , Oligonucleotídeos Antissenso/farmacologia , Proteínas Serina-Treonina Quinases , Estrutura Terciária de Proteína/efeitos dos fármacos , Estrutura Terciária de Proteína/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Leveduras/efeitos dos fármacos , Leveduras/genética , Leveduras/metabolismo , Receptor fas/efeitos dos fármacos , Receptor fas/genética , Receptor fas/metabolismoRESUMO
Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.
Assuntos
Mutação , Neoplasias Experimentais/prevenção & controle , RNA , Telomerase/antagonistas & inibidores , Telomerase/genética , Apoptose , Neoplasias da Mama , Domínio Catalítico/genética , Divisão Celular , Neoplasias do Colo , Proteínas de Ligação a DNA , Desenho de Fármacos , Feminino , Vetores Genéticos , Humanos , Neoplasias Experimentais/enzimologia , Neoplasias Ovarianas , Retroviridae/genética , Inibidores da Transcriptase Reversa , Telômero/metabolismo , Células Tumorais CultivadasRESUMO
For the past decade, cellular oncogenes have attracted the attention of biologists intent on understanding the molecular origins of cancer. As the present decade unfolds, oncogenes are yielding their place at center stage to a second group of actors, the tumor suppressor genes, which promise to teach us equally important lessons about the molecular mechanisms of cancer pathogenesis.
Assuntos
Genes Supressores de Tumor , Mapeamento Cromossômico , Neoplasias do Colo/genética , Genes da Neurofibromatose 1 , Genes do Retinoblastoma , Humanos , Neurofibromatose 1/genética , Retinoblastoma/genética , Proteína Supressora de Tumor p53/genética , Tumor de Wilms/genéticaRESUMO
As many as 40 distinct oncogenes of viral and cellular origin have been identified to date. Many of these genes can be grouped into functional classes on the basis of their effects on cellular phenotype. These groupings suggest a small number of mechanisms of action of the oncogene-encoded proteins. Some data suggest that, in the cytoplasm, these proteins may regulate levels of critical second messenger molecules; in the nucleus, these proteins may modulate the activity of the cell's transcriptional machinery. Many of the gene products can also be related to a signaling pathway that determines the cell's response to growth-stimulating factors. Because some of these genes are expressed in nongrowing, differentiated cells, the encoded proteins may in certain tissues mediate functions that are unrelated to cellular growth control.
Assuntos
Oncogenes , Animais , Aves , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Galinhas , Citoplasma/metabolismo , Vírus de DNA Tumorais/genética , Deltaretrovirus/genética , Drosophila , Fator de Crescimento Epidérmico/fisiologia , Substâncias de Crescimento/fisiologia , Guanosina Trifosfato/metabolismo , Humanos , Mutação , Neoplasias/genética , Fator de Crescimento Derivado de Plaquetas/fisiologia , Polyomavirus/genética , Proto-Oncogenes , Ratos , Sequências Repetitivas de Ácido Nucleico , Retroviridae/genética , Vírus 40 dos Símios/genética , Transcrição GênicaRESUMO
Two dozen cellular proto-oncogenes have been discovered to date through the study of retroviruses and the use of gene transfer. They form a structurally and functionally heterogeneous group. At least five distinct mechanisms are responsible for their conversion to active oncogenes. Recent work provides experimental strategies by which many of these oncogenes, as well as oncogenes of DNA tumor viruses, may be placed into functional categories. These procedures may lead to definition of a small number of common pathways through which the various oncogenes act to transform cells.
Assuntos
Neoplasias/etiologia , Oncogenes , Retroviridae/genética , Regulação da Expressão Gênica , Genes Virais , Humanos , Neoplasias/genética , Distribuição Tecidual , TransfecçãoRESUMO
Closed-circular proviral DNA of Moloney leukemia virus has been purified from a 10(7) excess of cellular and mitochondrial DNA. The DNA can be visualized in the electron microscope and has the contour length of a molecule with a moleculecular weight of about 5.5 + 10(6). Electron microscopic observation of a hybrid between viral RNA and this circular DNA confirms the viral origin of this molecule.
Assuntos
DNA Circular/isolamento & purificação , DNA Viral/isolamento & purificação , Vírus da Leucemia Murina de Moloney/análise , Microscopia Eletrônica , Vírus da Leucemia Murina de Moloney/crescimento & desenvolvimento , Hibridização de Ácido Nucleico , RNA Viral , RibonucleasesRESUMO
The responses of retinoblastoma tumor cells and normal retinal cells to various growth inhibitory factors were examined. Whereas fetal retinal cells were highly sensitive to the antimitogenic effects of transforming growth factor beta 1 (TGF-beta 1), retinoblastoma tumor cell lines were all resistant to this factor. Binding assays and affinity labeling of these cells with radioiodinated TGF-beta 1 revealed that the cells did not have TGF-beta receptors. The retinoblastoma cells lacked the three affinity-labeled proteins of 65, 95, and 300 kilodaltons typically seen in human cell lines and thus differed from normal retinal cells and from other types of neuroectodermal tumors that display the normal pattern of receptors. Loss of TGF-beta receptors, which is a rare event among tumor cells, may represent one mechanism through which these cells escape from negative control and form retinoblastomas.
Assuntos
Peptídeos/fisiologia , Receptores de Superfície Celular/fisiologia , Retinoblastoma/fisiopatologia , Divisão Celular , Linhagem Celular , Humanos , Receptores de Fatores de Crescimento Transformadores beta , Retina/citologia , Retinoblastoma/patologia , Fatores de Crescimento TransformadoresRESUMO
The autocrine model postulates that constitutive release of a mitogenic growth factor can lead to uncontrolled proliferation and cell transformation. A synthetic polynucleotide encoding epidermal growth factor conferred a tumorigenic phenotype on cells. These cells were transformed through the action of an autocrine circuit having an extracellular component.
Assuntos
Transformação Celular Neoplásica , Fator de Crescimento Epidérmico/genética , Oncogenes , Animais , Anticorpos Monoclonais , Divisão Celular , Transformação Celular Neoplásica/patologia , DNA Recombinante , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/imunologia , Regulação da Expressão Gênica , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Ratos , TransfecçãoRESUMO
The human cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma cell line EJ was localized on the short arm of human chromosome 11 by Southern blot analysis of human-rodent hybrid cell DNA. This locus contains human sequences homologous to the Harvey murine sarcoma virus v-Ha-ras oncogene.
Assuntos
Cromossomos Humanos 6-12 e X , Oncogenes , Neoplasias da Bexiga Urinária/genética , Linhagem Celular , Mapeamento Cromossômico , Enzimas de Restrição do DNA , Humanos , Células Híbridas , Hibridização de Ácido NucleicoRESUMO
A human colonic adenocarcinoma transforming gene, recently identified as a cellular homolog of the Kirsten sarcoma gene (v-ras), was used to assign the human cellular Kirsten ras2 gene to chromosome 12 by the Southern hybridization method. A single 640 base-pair Eco RI--Hind III fragment of the transforming gene, isolated by DNA transfection and molecular cloning, can detect a single Eco RI fragment (2.9 kilobase pairs) of DNA from phenotypically normal cells. The data suggest a constant chromosomal location of c-Ki-ras2.
Assuntos
Cromossomos Humanos 6-12 e X , Oncogenes , Adenocarcinoma/genética , Mapeamento Cromossômico , Neoplasias do Colo/genética , Humanos , Células Híbridas , Vírus do Sarcoma Murino de Kirsten/genética , Hibridização de Ácido Nucleico , Proto-Oncogene MasRESUMO
The retinoblastoma (Rb) antioncogene encodes a nuclear phosphoprotein, p105-Rb, that forms protein complexes with the adenovirus E1A and SV40 large T oncoproteins. A novel, aberrant Rb protein detected in J82 bladder carcinoma cells was not able to form a complex with E1A and was less stable than p105-Rb. By means of a rapid method for the detection of mutations in Rb mRNA, this defective Rb protein was observed to result from a single point mutation within a splice acceptor sequence in J82 genomic DNA. This mutation eliminates a single exon and 35 amino acids from its encoded protein product.
Assuntos
Neoplasias Oculares/genética , Mutação , Oncogenes , Fosfoproteínas/genética , Retinoblastoma/genética , Proteínas Precoces de Adenovirus , Antígenos Transformantes de Poliomavirus , Sequência de Bases , Proteínas de Ligação a DNA/metabolismo , Humanos , Dados de Sequência Molecular , Proteínas Oncogênicas Virais/metabolismo , Fosfoproteínas/metabolismo , Proteína do RetinoblastomaRESUMO
The neu oncogene, identified in ethylnitrosourea-induced rat neuroglioblastomas, had strong homology with the erbB gene that encodes the epidermal growth factor receptor. This homology was limited to the region of erbB encoding the tyrosine kinase domain. It was concluded that the neu gene is a distinct novel gene, as it is not coamplified with sequences encoding the EGF receptor in the genome of the A431 tumor line and it maps to human chromosome 17.
Assuntos
Antígenos de Neoplasias/genética , DNA de Neoplasias/genética , Proteínas de Neoplasias/genética , Oncogenes , Receptores de Superfície Celular/genética , Animais , Mapeamento Cromossômico , Cromossomos Humanos 16-18 , Receptores ErbB , Genes , Ligação Genética , Humanos , Neuroblastoma/genética , Neuroglia , RatosRESUMO
Rare diseases often provide unique and fascinating insights into the workings of biological machinery. Retinoblastoma is a good example. This hereditary disease occurs rarely (in only one out of 20,000 children), yet it opens a 'window' into the mechanisms that sit at the very center of growth control in cells throughout the body. Children who survive bilateral retinoblastoma often have offspring who are similarly affected. Indeed, transmission of the disease suggests the actions of a simple dominant Mendelian allele of high penetrance. Three years ago the wild-type allele of this gene (termed Rb) was isolated by molecular cloning. With this success has come a rich harvest of information on tumor pathogenesis and the molecular biology of cellular growth control.
Assuntos
Divisão Celular/genética , Neoplasias Oculares/genética , Retinoblastoma/genética , Criança , HumanosRESUMO
Increasing attention has been focused on how the retinoblastoma (RB) protein regulates cell growth. Recent evidence indicates that it is a substrate for phosphorylation by cyclin-dependent kinase-cyclin complexes and suggests that this phosphorylation modulates the ability of this protein to regulate transit through the cell cycle, perhaps in its G1 phase.
Assuntos
Ciclo Celular/fisiologia , Proteína do Retinoblastoma/fisiologia , Animais , Divisão Celular , Ciclinas/fisiologia , Genes do Retinoblastoma/fisiologia , Humanos , Fosforilação , Transdução de Sinais/fisiologiaRESUMO
The proliferation of cells is regulated by countervailing positively- and negatively-acting signaling networks. The anti-proliferative signals, the study of which has been much neglected until recently, are often conveyed by growth-inhibitory peptides. Elements that mediate the cellular response to growth inhibitors are encoded by tumor suppressor genes that if lost may lead to the runaway growth of the cancer cell.
Assuntos
Genes Supressores de Tumor , Inibidores do Crescimento/genética , Transdução de Sinais , Fator de Crescimento Transformador betaRESUMO
The mutation of tumor suppressor genes is thought to contribute to tumor growth by inactivating proteins that normally act to limit cell proliferation. Several tumor suppressor proteins have been identified in recent years, but only two of them, p53 and pRb, are understood in detail. In the past year, a role has become apparent for both of these proteins in transcription and phosphorylation events required for passage of a cell from G1 to S phase. The pRb protein appears to prevent the function of transcription factors and other proteins needed for S phase until its inactivation by cyclin-dependent kinases in late G1. Induction of p53 by DNA damage may act to cause cell cycle arrest or cell death by altering the transcription program of damaged cells. A detailed molecular understanding of these growth regulators is now emerging, and is the subject of this review.