"Nutritional and chemopreventive anti-cancer agents up-regulate expression of p27Kip1, a cyclin-dependent kinase inhibitor, in mouse JB6 epidermal and human MCF7, MDA-MB-321 and AU565 breast cancer cells"

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Abstract

  • Background: p27(Kip1) is a cyclin-dependent kinase inhibitor. When up-regulated, p27 inhibits GI-to-S phase transition of the cell cycle. This report addresses the question of whether various nutritional and chemopreventive anti-cancer agents up-regulate the expression of p27 in preneoplastic and neoplastic cells. Results: Experimental evidence presented in the first half of this report shows that these agents fairly faithfully up-regulate expression of p27 in mouse epidermal (JB6) and human breast cancer (MCF7, MDA-MB-321, and AU565) cells. Up-regulation appears to be specific to p27 because expression of cyclin DI, E, and A, and p21Cipl/Wafl was not modulated by these agents. Up-regulation of the expression of p27 is likely due to the activation of translation rather than transcription of p27 because (a) up-regulation is mediated by the 5′-untranslated region (-575) of the p27 gene and (b) the antibiotic actinomycin D, an inhibitor of transcription, did not attenuate the up-regulation of p27. This latter finding is likely to preclude the existence of cryptic transcription factor binding site(s) in the 5′-untranslated region of p27 gene. The experimental evidence, presented in the second half of this report, was obtained using the 5′-untranslated region (-575) of p27 gene. The evidence suggests that cancer preventive agents up-regulate expression of p27 by at least four different molecular signaling pathways: (a) Caloric restriction is likely to up-regulate p27 expression via 5′-AMP-activated protein kinase (AMPK; a metabolic energy sensor or cellular fuel gauge), tuberous sclerosis complex (TSC), and mammalian target of rapamycin (mTOR). Amino acid deficiencies also up-regulate the expression of p27 using some components of this pathway. (b) 4-Hydroxytamoxifen (but not tamoxifen), genistein (but not genistin), daidzein, and probably other nutritional and chemopreventive anti-cancer agents could up-regulate expression of p27 via receptor protein tyrosine kinases (RPTKs), phosphoinositide 3-kinase (P13K), phosphoinosite-dependent kinase (PDK), Akt/PKB and mTOR. (c) Expression of p27 could also be up-regulated via RPTKs followed by MAPKs - MEK, ERK and p38MAPK - and probably MNK. Finally, (d) global hypomethylation of 5′-m7G cap of mRNAs could also up-regulate expression of p27. Conclusion: Based on these findings, we conclude that various nutritional and chemopreventive anti-cancer agents up-regulate expression of p27 in (pre)neoplastic cells. © 2006 Eto; licensee BioMed Central Ltd.
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  • Eto I
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  • 6