人类胶质瘤中G1期阻滞途径的突变建模：CDK4的过表达而非INK4a-ARF的缺失在培养的小鼠星形胶质细胞中诱导超倍体形成。
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.
作者信息
Holland E C, Hively W P, Gallo V, Varmus H E
机构信息
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892 USA.
出版信息
Genes Dev. 1998 Dec 1;12(23):3644-9. doi: 10.1101/gad.12.23.3644.
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 CDK4 amplification and INK4a-ARF loss in gliomagenesis, we compared the behavior of astrocytes lacking a functional INK4a-ARF locus with astrocytes overexpressing CDK4. Either a deficiency of p16(INK4a) and p19(ARF) or an increase in Cdk4 allows cultured astrocytes to grow without senescence. Astrocytes overexpressing CDK4 grow more slowly than INK4a-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.
摘要
几乎所有人类胶质瘤在控制G1期停滞的三个基因位点之一中都表现出改变：INK4a-ARF、CDK4或RB。为了辨别CDK4扩增和INK4a-ARF缺失在胶质瘤发生中的作用，我们将缺乏功能性INK4a-ARF位点的星形胶质细胞与过表达CDK4的星形胶质细胞的行为进行了比较。p16(INK4a)和p19(ARF)的缺陷或Cdk4的增加都能使培养的星形胶质细胞在无衰老的情况下生长。过表达CDK4的星形胶质细胞比INK4a-ARF缺陷的星形胶质细胞生长得更慢，并高效地转变为四倍体状态；相比之下，INK4a-ARF缺陷的细胞保持假二倍体状态，这与在这些基因中具有相应损伤的人类胶质瘤中观察到的特性一致。
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