Asunto(s)
Antígenos Transformadores de Poliomavirus/genética , Ratones Transgénicos/genética , Ratones Transgénicos/virología , Virus 40 de los Simios/genética , Animales , ADN Viral/administración & dosificación , ADN Viral/genética , ADN Viral/aislamiento & purificación , Modelos Animales de Enfermedad , Femenino , Genes Virales , Vectores Genéticos , Humanos , Masculino , Ratones , Ratones Transgénicos/inmunología , Microinyecciones , Oncogenes , Fenotipo , Virus 40 de los Simios/inmunología , Transformación GenéticaRESUMEN
Cellular responses to environmental stimuli are controlled by a series of signaling cascades that transduce extracellular signals from ligand-activated cell surface receptors to the nucleus. Although most pathways were initially thought to be linear, it has become apparent that there is a dynamic interplay between signaling pathways that result in the complex pattern of cell-type specific responses required for proliferation, differentiation and survival. One group of nuclear effectors of these signaling pathways are the Ets family of transcription factors, directing cytoplasmic signals to the control of gene expression. This family is defined by a highly conserved DNA binding domain that binds the core consensus sequence GGAA/T. Signaling pathways such as the MAP kinases, Erk1 and 2, p38 and JNK, the PI3 kinases and Ca2+-specific signals activated by growth factors or cellular stresses, converge on the Ets family of factors, controlling their activity, protein partnerships and specification of downstream target genes. Interestingly, Ets family members can act as both upstream and downstream effectors of signaling pathways. As downstream effectors their activities are directly controlled by specific phosphorylations, resulting in their ability to activate or repress specific target genes. As upstream effectors they are responsible for the spacial and temporal expression or numerous growth factor receptors. This review provides a brief survey of what is known to date about how this family of transcription factors is regulated by cellular signaling with a special focus on Ras responsive elements (RREs), the MAP kinases (Erks, p38 and JNK) and Ca2+-specific pathways and includes a description of the multiple roles of Ets family members in the lymphoid system. Finally, we will discuss other potential mechanisms and pathways involved in the regulation of this important family of transcription factors.
Asunto(s)
Proteínas de Unión al ADN , Familia de Multigenes , Proteínas Represoras , Transducción de Señal , Factores de Transcripción/fisiología , Animales , Calcio/metabolismo , Señalización del Calcio/genética , Señalización del Calcio/fisiología , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Elementos de Facilitación Genéticos , Predicción , Hematopoyesis/genética , Humanos , Transporte Iónico/genética , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Modelos Biológicos , Fosforilación , Poliomavirus/genética , Poliomavirus/fisiología , Canales de Potasio/fisiología , Proteínas Quinasas/fisiología , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Proteína Proto-Oncogénica c-ets-2 , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-ets , Transducción de Señal/genética , Transducción de Señal/fisiología , Transactivadores/genética , Transactivadores/fisiología , Factores de Transcripción/genética , Proteína Elk-1 con Dominio ets , Proteínas ras/fisiologíaRESUMEN
Cyclin D expression is regulated by growth factors and is necessary for the induction of mitogenesis. Herbimycin A, a drug that binds to Hsp90, induces the destruction of tyrosine kinases and causes the down-regulation of cyclin D and an Rb-dependent growth arrest in the G1 phase of the cell cycle. We find that the induction of D-cyclin expression by serum and its repression by herbimycin A are regulated at the level of mRNA translation. Induction of cyclin D by serum occurs prior to the induction of its mRNA and does not require transcription. Herbimycin A repression is characterized by a decrease in the synthetic rate of D-cyclins prior to changes in mRNA expression and in the absence of changes in the half-life of the protein. This effect on D-cyclin translation is mediated via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. PI 3-kinase inhibitors such as wortmannin and LY294002, and rapamycin, an inhibitor of FRAP/TOR, cause a decline in the level of D-cyclins, whereas inhibitors of mitogen-activated protein kinase kinase and farnesyltransferase do not. Cells expressing the activated, myristoylated form of Akt kinase, a target of PI 3-kinase, are refractory to the effects of herbimycin A or serum starvation on D-cyclin expression. These data suggest that serum induction of cyclin D expression results from enhanced translation of its mRNA and that this results from activation of a pathway that is dependent upon PI 3-kinase and Akt kinase.
Asunto(s)
Ciclinas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Oncogénicas de Retroviridae/metabolismo , Benzoquinonas , Ciclina D , Ciclinas/genética , Humanos , Lactamas Macrocíclicas , Proteína Oncogénica v-akt , Inhibidores de las Quinasa Fosfoinosítidos-3 , Biosíntesis de Proteínas , Quinonas/farmacología , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rifabutina/análogos & derivados , Células Tumorales CultivadasRESUMEN
The T-cell-specific protooncogene lck, a src-related tyrosine kinase, is under the control of two promoters that give rise to transcripts differing only in their 5'-untranslated regions. The distal promoter is transcriptionally active in both peripheral and thymic T-cells, whereas expression of the proximal promoter is highest in developing thymocytes. The proximal promoter has also been shown to be selectively activated in a number of colon carcinoma cell lines. Approximately 570 base pairs of proximal promoter sequence is required for expression in both T-cells and colon carcinoma cell lines. Protein binding studies were initiated with an oligonucleotide homologous to a region that, when deleted, causes an increase in promoter activity in transgenic animals. Two proteins with approximate molecular masses of 35 and 75 kDa were found to bind to this region as determined by UV cross-linking studies. Absence of specific protein binding is correlated with a high level of proximal promoter expression. Competitive gel retardation analysis identified a 9-base pair binding site within the proximal lck promoter that is necessary for repression of transcription in cells that contain specific binding activity. Mutants of this binding site do not repress transcription. Repression does not occur in a cell line that expresses lck and lacks this activity. These data support the hypothesis that activation of lck transcription in colon carcinoma is due, at least in part, to the loss of a transcriptional repressor.