RESUMEN
The activated tyrosine kinase, Bcr-abl, is implicated in a number of hematopoietic malignancies. The exact biological mechanism by which the kinases transforms cells is still not well delineated. Previous data has suggested that the inhibition of apoptosis and the deregulation of cell cycle progression as the result of P210Bcr-abl expression might contribute to leukemogenesis. In vitro systems in which Bcr-Abl is over-expressed have concluded that similar growth regulatory pathways are affected as a result of the expression of both P210 and P190Bcr-abl. Here, we utilized an in vitro P190Bcr-abl leukemia mouse model to dissect the early events that contribute to transformation by this isoform of Bcr-Abl. In this mouse model P190Bcr-abl is expressed as a low but physiologically relevant level in that all mice develop pre-B leukemia lymphomas. We show that cell cycle and apoptotic responses to DNA damage are intact in bone marrow and spleen cells of such animals. We also demonstrate a normal induction of p21WAF-1/CIP1 in both hematopoietic and non-hematopoietic tissue as a result of genotoxic stress. We suggest that P190Bcr-abl induced transformation is different than that of P210Bcr-abl.
Asunto(s)
Ciclo Celular/genética , Ciclinas/metabolismo , Proteínas de Fusión bcr-abl/genética , Leucemia/genética , Animales , Anticuerpos/farmacología , Apoptosis/genética , Apoptosis/efectos de la radiación , Médula Ósea/patología , Médula Ósea/fisiología , Médula Ósea/efectos de la radiación , Complejo CD3/inmunología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Factor Estimulante de Colonias de Granulocitos/farmacología , Interleucina-2/farmacología , Pulmón/patología , Pulmón/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Lesiones Precancerosas , Bazo/patología , Bazo/fisiología , Bazo/efectos de la radiación , Irradiación Corporal TotalRESUMEN
The acquisition of the Philadelphia (Ph) chromosome (or BCR-ABL translocation) represents a detrimental pathophysiological event in humans. The activated tyrosine kinases, which are produced by this translocation, are associated with fatal hematological malignancies. The initial molecular dissection of BCR-ABL has linked the expression of this constitutively activated kinase with enhanced genomic instability. We directly evaluated the consequence of BCR-ABL expression on genomic instability using the Big Blue in vivo mutagenesis mouse system. We report that the expression of BCR-ABL in both spleens and kidneys confers a mutator phenotype represented by a statistically significant elevation in mutant frequencies.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Proteínas Tirosina Quinasas/metabolismo , Animales , Activación Enzimática , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutagénesis , Bazo/metabolismoRESUMEN
Studies of the molecular biology of human papillomavirus type 16 have been limited by the lack of a tissue culture system that is fully permissive for virus replication; as a result, high-titre stocks of infectious virus are not readily available. Therefore, studies of viral gene expression have relied on analysis of transformed or tumour cell lines harbouring latent or integrated viral genomes, or on the behaviour of transfected reporter gene constructs. To provide a method of efficiently delivering papillomavirus information into the nuclei of mammalian cells, we constructed a herpes simplex virus type 1 recombinant bearing the entire human papillomavirus type 16 genome. The resulting recombinant was capable of lytic replication and induced the accumulation of papillomavirus mRNAs initiated from the p97 early promoter during infection of Vero cells. This and other herpes simplex - papillomavirus recombinants should facilitate molecular analysis of the life cycle of human papillomavirus type 16.