A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis
A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis
复制标题
DOI：
10.1073/pnas.0407693101
复制
发表时间：
2004-12-07
影响因子：
11.1
通讯作者：
Abate-Shen, C
中科院分区：
文献类型：
--
作者：
Gao, H;Ouyang, X;Abate-Shen, C
在非人前列腺癌中，p27（kip 1）蛋白表达的频繁下调与不良的临床结果相关，然而p27（kip 1）很少经历突变失活。在这里，我们调查的后果，减少或消除p27（kip 1）功能的背景下，缺乏Nkx3.1同源框基因和Pten肿瘤抑制基因的小鼠模型前列腺癌的发生。出乎意料的是，我们发现对于P27（kip 1）无效等位基因杂合的三重突变小鼠（Nkx3.1（+/-）或（-/-）; Pten（+/-）; p27（+/-））显示增强的前列腺癌发生，而对于p27（kip 1）纯合无效的小鼠（Nkx3.1（+/-）或（-/-）; Pten（+/-）; P27（-/-））显示癌症进展的抑制。表达谱分析表明，细胞周期蛋白D1是高度上调的复合p27（kip 1）杂合子，但下调的复合p27（kip 1）纯合子突变体。使用RNA干扰在前列腺癌细胞系与不同的p27（kip 1）基因剂量，我们表明，前列腺致瘤性取决于p27（kip 1）的水平和p27（kip 1）基因剂量的后果可以部分归因于细胞周期蛋白D1水平的改变。我们的研究结果表明，p27（kip 1）在前列腺癌的进展中具有剂量敏感的积极和消极的调节作用。
Inhuman prostate cancer, the frequent down-regulation of p27(kip1) protein expression is correlated with poor clinical outcome, yet p27(kip1) rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27(kip1) function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a P27(kip1) null allele (Nkx3.1(+/-) or (-/-); Pten(+/-); p27(+/-)) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27(kip1) (Nkx3.1(+/-) or (-/-); Pten(+/-); P27(-/-)) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27(kip1) heterozygotes, but is down-regulated in the compound p27(kip1) homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27(kip1) gene doses, we show that prostate tumorigenicity depends on levels of p27(kip1) and that the consequences of p27(kip1) gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27(kip1) possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression.