Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer, fibrotic diseases and arteriosclerosis. The PDGF family ...currently consists of at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectively signal through two PDGF receptors (PDGFRs) to regulate diverse cellular functions. After two decades of searching, PDGF-A and B were the only ligands identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family, PDGF-C, a functional analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDGF-C selectively activate PDGFR-α, whereas PDGF-B activates both PDGFR-α and PDGFR-β. Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activation. Recombinant, purified PDGF-D induces DNA synthesis and growth in cells expressing PDGFRs. In cells expressing individual PDGFRs, PDGF-D binds to and activates PDGFR-β but not PDGFR-α. However, in cells expressing both PDGFRs, PDGF-D activates both receptors. This indicates that PDGFR-α activation may result from PDGFR-α/β heterodimerization.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
RESUMEN Introducción: El estudio de la ocurrencia de la tuberculosis en los territorios geográficos es importante para guiar a los decisores en las intervenciones diferenciadas. Objetivo: Evaluar las ...desigualdades en la ocurrencia de tuberculosis y de algunas variables sociodemográficas individuales entre las regiones geográficas cubanas. Métodos: Estudio ecológico de series temporales combinado con un estudio descriptivo sobre el número de casos y las tasas de incidencia de tuberculosis en Occidente, Centro y Oriente. Obtuvimos la información de la base de datos nacional de vigilancia de tuberculosis. Calculamos las tasas de incidencia y sus medias geométricas, la menor fue referencia para calcular las diferencias absolutas y relativas. Estimamos las tendencias de las incidencias regionales y las proporciones de algunas variables individuales. Resultados: La región oriental mostró la menor media geométrica de las tasas (5,2) y fue la referencia: su tendencia resultó descendente con reducción total de 22,6 %. En la incidencia predominaron los hombres de 15-64 años en las tres regiones (63,8 %). Los menores de 15 años estuvieron entre 0,4-1,3 %. La región oriental presentó menos defunciones (25,9 %). La occidental aportó 44,2 % de la tuberculosis pulmonar y 46,3 % del diagnóstico bacteriológico. Conclusiones: La región occidental presentó las desigualdades más importantes y mayor riesgo en la ocurrencia de tuberculosis. Se debe profundizar en el análisis de los determinantes individuales posiblemente relacionados y realizar intervenciones diferenciadas.
The fibroblast growth factor (FGF) family of signaling molecules has been implicated in normal developmental and physiological processes, as well as in human malignancy. Using a homology-based ...genomic DNA mining process, we identified a human gene encoding a novel member of the FGF family, that we designate FGF-20. The FGF-20 cDNA was isolated, and its sequence confirmed the gene prediction. FGF-20 is expressed in normal brain, particularly the cerebellum, and in some cancer cell lines. Recombinant FGF-20 protein induces DNA synthesis in a variety of cell types and is recognized by multiple FGF receptors. Ectopic expression of FGF-20 in NIH 3T3 cells renders the cells transformed in vitro and tumorigenic in nude mice. These results underscore the utility of mining genomic DNA databases and reveal FGF-20 to be a novel oncogene that may play a role in human cancer.
A 50-kDa cellular factor, E4F, has been implicated in mediating trans activation of the adenovirus E4 gene by the 289R E1A
(13S)
protein. Previous experiments demonstrated an E1A-dependent increase ...in E4F DNA binding activity, dependent on phosphorylation, that correlated with the activation of E4 transcription. Using expression screening, we isolated a cDNA clone encoding the E4F protein, as judged by DNA binding characteristics, transcriptional activation, and immunological criteria. The E4F-1 cDNA encodes a 783-amino-acid polypeptide that has 86% sequence identity with the murine nuclear factor ϕAP3, a GLI-krüppel-related protein. E4F DNA binding activity is encoded within an amino-terminal region of E4F-1 that contains a zinc finger domain and, as with endogenous E4F, is phosphatase sensitive. We found that E4F was generated from the full-length E4F-1-encoded protein as a 50-kDa amino-terminal fragment. Moreover, E1A
(13S)
expression induced the phosphorylation of both forms of E4F-1 but differentially regulated their DNA binding activities, stimulating the 50-kDa fragment while reducing the activity of the full-length protein. In transient-transfection assays, the E4F-1 amino-terminal fragment stimulated the adenovirus E4 promoter in the presence of E1A
(13S)
, whereas the full-length protein repressed the promoter in the absence, but not the presence, of E1A. The results indicate that the 50-kDa polypeptide responsible for E4F DNA binding activity is a fragment generated from the human homolog of ϕAP3 and that the two forms of the E4F-1 protein are differentially regulated by E1A through phosphorylation.
p50E4F is a cellular transcription factor whose DNA binding activity is stimulated in a phosphorylation-dependent manner by products of the adenovirus E1A oncogene. Although p50E4F does not contain a ...bZIP DNA binding motif, it binds a tandemly repeated palindromic sequence in the adenovirus E4 promoter that is recognized by a large number of bZIP proteins, but with much greater stability. Analysis of deletions in the p50E4F sequence identified the regions that are responsible for its unique DNA binding properties. Sequence-specific DNA binding and factor dimerization were localized to a C-terminal region containing two C2H2 and one CCHC zinc finger motifs; the phosphorylation site critical for DNA binding activity was also localized to this domain. The high stability of p50E4F binding also required residues within the first 83 amino acids of the N-terminus. Analysis of single and double amino acid substitutions in the C-terminal zinc finger domain demonstrated that while the second C2H2 zinc finger was required for DNA binding activity, the putative structures of the first C2H2 and the CCHC zinc fingers were not. Instead, residues from these other zinc finger motifs appeared to participate in an alternative structure that mediates DNA binding activity and is regulated by phosphorylation.
Adenovirus E1A proteins influence cell growth and phenotype through physical interactions with cellular proteins that regulate basic processes such as cell cycle progression, DNA synthesis, and ...differentiation. p120E4F is a low-abundance cellular transcription factor that represses the adenovirus E4 promoter and is regulated by E1A, through a phosphorylation-induced reduction of its DNA binding activity, to permit activation of the E4 promoter during early infection. To determine the normal biological role of p120E4F, we assessed its ability to influence fibroblast cell growth and transformation. p120E4F suppressed NIH 3T3 fibroblast colony formation but had little effect when coexpressed with E1A and/or activated ras. Cells that overexpressed p120E4F were inhibited in their ability to enter S phase, had elevated levels of the cdk inhibitor p21WAF1, and reduced cyclin D-cdk4/6 kinase activity. The increase of p21WAF1 levels occurred through a p53-independent posttranscriptional mechanism that included a three- to fourfold increase in the half-life of p21WAF1 protein. Coexpression of activated ras with p120E4F stimulated cyclin D1 expression, elevated cyclin D-cdk4/6 kinase activity, and accelerated cell growth. These data suggest an important role for p120E4F in normal cell division and demonstrate that p21WAF1 can be regulated by protein turnover.
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