Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer.
Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer.
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DOI：
10.1038/onc.2009.226
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发表时间：
2009-10-15
期刊：
影响因子：
8
通讯作者：
Kemp, C. J.
中科院分区：
文献类型：
--
作者：
Kelly-Spratt, K. S.;Philipp-Staheli, J.;Gurley, K. E.;Hoon-Kim, K.;Knoblaugh, S.;Kemp, C. J.
Reduced expression of the CDK inhibitor p27Kip1 (p27) in human lung cancer correlates with tumour aggressiveness and poor prognosis. However, the regulation of p27 expression and the role of p27 during lung cancer are poorly understood. Urethane-induced lung tumours in mice frequently harbor mutations in the Kras oncogene and here we use this model to address the regulation of p27 during tumorigenesis. The Ras effector Akt is known to regulate p27 mRNA abundance by phosphorylating and inactivating the FOXO transcription factors. Phosphorylated Akt and FOXO proteins were both increased in lung tumours, correlating with a reduction in p27 mRNA transcript. Akt also directly phosphorylates p27 and regulates its nuclear/cytoplasmic localization. Tumours showed a reduced nuclear/cytoplasmic ratio of p27 protein, together with an increase in phosphorylated Thr198 p27 in the cytoplasmic pool. Treatment of lung tumour-bearing mice with the phosphoinositol-3 kinase inhibitor LY294002 induced a rapid decrease in phosphorylated Akt and phosphorylated p27, concomitant with an increase in nuclear p27. Germline p27 deficiency accelerated both the growth and malignant progression of urethane-induced lung tumours, and did so in a cell autonomous manner, confirming a causal role of p27 in tumour suppression. These results demonstrate that p27 is a potent barrier to the growth and malignant progression of Kras-initiated lung tumours. Further, the reduction of nuclear p27 in tumours is mediated by oncogene signaling pathways, which can be reversed by pharmacologic agents.
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