Modeling mutations in the G1 arrest pathway in human gliomas: overexpression of CDK4 but not loss of INK4a–ARF induces hyperploidy in cultured mouse astrocytes

Abstract

Nearly all human gliomas exhibit alterations in one of three genetic loci governing G1 arrest: INK4a–ARF,CDK4, or RB. To discern the roles of CDK4amplification and INK4a–ARF loss in gliomagenesis, we compared the behavior of astrocytes lacking a functional INK4a–ARFlocus with astrocytes overexpressing CDK4. Either a deficiency of p16INK4a and p19ARF or an increase in Cdk4 allows cultured astrocytes to grow without senescence. Astrocytes overexpressing CDK4 grow more slowly thanINK4a–ARF-deficient astrocytes and convert to a tetraploid state at high efficiency; in contrast, INK4a–ARF-deficient cells remain pseudodiploid, consistent with properties observed in human gliomas with corresponding lesions in these genes.