Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced expression of the CDK inhibitor p27(Kip1) (p27) in human lung cancer correlates with tumor aggressiveness and poor prognosis. However, the regulation of p27 expression and the role of p27 during lung cancer are poorly understood. Urethane-induced lung tumors in mice frequently harbor mutations in the Kras oncogene, and in this study, 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 tumors, correlating with a reduction in p27 mRNA transcript. Akt also directly phosphorylates p27 and regulates its nuclear/cytoplasmic localization. Tumors showed a reduced nuclear/cytoplasmic ratio of p27 protein, together with an increase in phosphorylated Thr197 p27 in the cytoplasmic pool. Treatment of lung tumor-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 tumors, and did so in a cell autonomous manner, confirming a causal role of p27 in tumor suppression. These results show that p27 is a potent barrier to the growth and malignant progression of Kras-initiated lung tumors. Further, the reduction of nuclear p27 in tumors is mediated by oncogene signaling pathways, which can be reversed by pharmacological agents.
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PMID:Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer. 1964 63

Ethyl carbamate (EC) is a multi-site carcinogen in experiment animals and probably carcinogenic to humans (IARC group 2A). The present study was designed to investigate the cytotoxicity effect of EC on human hepatoma G2 (HepG2) cells. The results revealed that EC inhibited the viability of HepG2 cells significantly in a dose-dependent manner. Further analysis indicated that high concentration of EC induced cell apoptosis, inhibited the G1 to S phase transition along with increased expression of p53 and p21 and decreased the expression of cyclin E and Cdk 2, but no significant change in p27 expression was observed, which were evidenced by both real time PCR and western blotting analyses. Moreover, the results of the DCFH-DA assay suggested that oxidative stress was involved in the cytotoxic effects of EC. Altogether, the present work indicated that p21, cyclin E and Cdk2, which were regulated by p53, might account for the effect of EC on cell viability and cell cycle arrest, but p27 was not involved in the pathway in HepG2 cells treated with EC.
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PMID:In vitro toxicological evaluation of ethyl carbamate in human HepG2 cells. 3009 Mar 83