Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Neoplasias Primárias Múltiplas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Análise Mutacional de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , Saúde da Família , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo Genético , Supressão GenéticaRESUMO
Within the past year, the draft sequence of the human genome was completed and made available to researchers worldwide. Recent advances in technology along with the vast amount of sequence data on the human genome now provide a previously unimagined means of defining the genetic architecture of cancer cells. Implicit in this approach is the ability to describe the evolution of that architecture as normal breast cells progress toward the malignant phenotype. Ongoing experiments involving the simultaneous analysis of the entire genome in a high-throughput manner are expected to reveal those genes and regulatory mechanisms that are critical at each step of progression toward malignancy, including (1) providing a growth advantage over normal cells, (2) maintaining the malignant state, (3) modulating response to therapy, and (4) developing metastatic potential. Once these data are available, the ability to design preventive, diagnostic, prognostic, and therapeutic tools directed at those targets will be within reach.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Antineoplásicos/farmacologia , DNA Complementar/genética , Progressão da Doença , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Investigation of the large POU domain family of developmental regulators has revealed a molecular mechanism by which highly related transcription factors sharing common DNA-binding motifs act to functionally discriminate their cognate DNA sequences. Studies of two classes of neuron-specific POU domain factors (III and IV) indicate that functional specificity on their native response elements is achieved by accommodating different nucleotide spacing between variably oriented bipartite core DNA-binding motifs. The preferred orientation of the POU-specific domain of the neuronal factors on their native response elements appears to be opposite that of Pit-1 and Oct-1. Members of POU-III (Brn-2) class exhibit remarkable flexibility in DNA site recognition (tolerating core motifs spaced by 0, 2, or 3 nucleotides), whereas POU-IV (Brn-3) class is highly constrained (tolerating core motifs with a spacing of 3 nucleotides). The molecular determinant of the constraint in DNA site selection appears to be imparted by 3 amino acid residues in the amino-terminal basic region in concert, with helix 2 of the POU homeo domain which together are involved in minor groove and possibly phosphate backbone contacts. Similar mechanisms may underlie differential flexibility in spacing and orientation for diverse families of transcription factors.
Assuntos
Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Hormônio Liberador da Corticotropina/genética , Proteínas de Homeodomínio , Dados de Sequência Molecular , Fatores do Domínio POU , Regiões Promotoras Genéticas , Ratos , Proteínas Recombinantes de Fusão , Transcrição GênicaRESUMO
Characterization of Brn-3.0 and identification of a highly related member (Brn-3.1) of the class IV POU-domain family suggest potential roles of Brn-3.0 in the development of retinal ganglion cells and sensory neurons, as well as potential roles in the pituitary gland and the immune system. Brn-3.0 is expressed in the pituitary gland and in a corticotroph cell line. A functional DNA response element has been identified in the proopiomelanocortin promoter. In contrast to previously described mammalian POU-domain proteins, Brn-3.0 binds relatively ineffectively to known octamer DNA motifs, but instead binds with high affinity to a distinct set of DNA elements, functioning as a transcriptional activator. Brn-3.0, Brn-3.1, and the Drosophila tI-POU share an N-terminal region of homology, referred to as the "POU-IV box," which is similar to a conserved functional domain in the c-myc gene family.
Assuntos
Proteínas de Ligação a DNA/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/genética , Fatores Etários , Animais , Sequência de Bases , Clonagem Molecular , Análise Mutacional de DNA , Primers do DNA/química , DNA Complementar/genética , Glândulas Endócrinas/embriologia , Glândulas Endócrinas/metabolismo , Expressão Gênica , Genes , Tecido Linfoide/embriologia , Tecido Linfoide/metabolismo , Camundongos/embriologia , Dados de Sequência Molecular , Família Multigênica , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Fator de Transcrição Brn-3 , Fator de Transcrição Brn-3ARESUMO
Nerve regeneration across a 10-mm gap was delayed in streptozotocin diabetic rats 3 and 4 weeks after transecting the sciatic nerve. Opposite ends of each cut nerve were introduced into a silicone tube, leaving a 10-mm gap. Electron microscopy was used to evaluate the progress of regeneration in sections at 2-mm intervals across the 10-mm gap. After 3 weeks, control axons had bridged the 10-mm gap, and myelin sheaths extended for 6-8 mm. By contrast, axons and their myelin sheaths were seen no further than 2 mm from the proximal stump in diabetic animals. By 4 weeks, axons had bridged the gap in diabetics; however, they appeared immature and showed dystrophic changes. The findings suggest that although regeneration does occur in diabetic nerves, it is significantly delayed and qualitatively impaired.
