Animal models of cell cycle dysregulation and the pathogenesis of gliomas

Mutations in gliomas, for the most part, fall into two main categories. The first category of mutations affects genes that produce proteins which acti vate signal transduction pathways downstream of tyrosine kinase receptors; the second category disrupts the pathways leading to cell cycle arrest. Cel l cycle arrest pathways normally maintain cells in the G1 phase of the cell cycle, preventing inappropriate proliferation. The role of disregulation o f these pathways in tumor formation is currently the focus of many investig ations. Studies carried out with astrocytes and other cell types indicate t hat these pathways may also function in maintenance of appropriate chromoso me number and differentiated phenotype, and in acquisition of senescence. G enetically defined mouse models of gliomagenesis have been helpful in incre asing our understanding of how cell cycle arrest pathways cooperate with al terations in signal transduction pathways to provoke tumor formation in man y cell types, including glial cells. Various strategies for experimental ce ll cycle arrest disruption show minimal or no formation of gliomas. In cont rast, gliomas are generated with a number of strategies that enhance signal transduction downstream of tyrosine kinase receptors. Experimental disrupt ion of the cell cycle arrest pathways is required for gliomagenesis in some of these models, but not in others. Furthermore in some cases, although no t required for gliomagenesis, disruption of the cell cycle arrest pathways appears to enhance glioma formation. The results of these mouse model exper iments imply a potentially complex role for cell cycle arrest disruption in human gliomagenesis.