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Title: cAMP-dependent cytosolic mislocalization of p27(kip)-cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma.

Authors: Cohen, Jennifer D; Tham, Kimberly Y; Mastrandrea, Nicholas J; Gallegos, Alfred C; Monks, Terrence J; Lau, Serrine S

Published In Toxicol Sci, (2011 Aug)

Abstract: The loss of tuberin, the tuberous sclerosis-2 (Tsc-2) gene product, is associated with cytoplasmic mislocalization of p27 in uterine leiomyomas derived from Eker rats (Tsc-2(EK/+)) and in human metastatic renal cell carcinoma tissue. Signaling associated with cytoplasmic mislocalization of p27 in renal cancer is relatively unknown. Renal tumors derived from 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ)-treated Tsc-2(EK/+) rats, and null for tuberin, display elevated nuclear and cytosolic p27, with parallel increases in cytosolic cyclin D1 levels. Similar changes are observed in TGHQ-transformed renal epithelial cells derived from Tsc-2(EK/+) rats (QTRRE cells), which, in addition to the cytoplasmic mislocalization of p27 and cyclin D1, exhibit high ERK, B-Raf, and Raf-1 kinase activity. Renal tumor xenografts, derived from subcutaneous injection of QTRRE cells into nude mice, also display increases in cytosolic mislocalization of p27 and cyclin D1. Dibutyryl cAMP and/or phosphodiesterase inhibitors (PIs; pentoxifylline or theophylline) increase Rap1B activation, B-Raf kinase activity, and cytosolic p27/cyclin D1 protein levels in QTRRE cells. Inhibition of Raf kinases with either sorafenib or B-Raf small interfering RNA (siRNA) caused a mitogen-activated protein kinase-mediated downregulation of p27. Moreover, decreases in cyclin D1 were also associated with p27 siRNA knockdown in QTRRE cells. Finally, theophylline-mediated increases in p27 and cyclin D1 were attenuated by sorafenib, which modulated Raf/MEK/ERK signaling. Collectively, these data suggest that the cAMP/Rap1B/B-Raf pathway modulates the expression of p27 and the cytoplasmic mislocalization of p27-cyclin D1 in tuberous sclerosis gene-regulated-renal cancer. Therefore, the loss of tuberin and engagement of the cAMP pathway may independently direct p27-cyclin D1 cytosolic stabilization during renal tumor formation.

PubMed ID: 21693435 Exiting the NIEHS site

MeSH Terms: Animals; Benzenesulfonates/metabolism; Bucladesine/pharmacology*; Carcinoma, Renal Cell/chemically induced*; Cell Line; Cyclin D1/genetics; Cyclin D1/metabolism*; Cyclin-Dependent Kinase Inhibitor p27/antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p27/genetics; Cyclin-Dependent Kinase Inhibitor p27/metabolism*; Cytosol/metabolism; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Glutathione/analogs & derivatives; Glutathione/pharmacology; Humans; Hydroquinones/pharmacology; Kidney Neoplasms/chemically induced*; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism; Pentoxifylline/metabolism; Phosphodiesterase Inhibitors/metabolism; Proto-Oncogene Proteins B-raf/metabolism; Proto-Oncogene Proteins c-raf/metabolism; Pyridines/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Rats; Signal Transduction; Theophylline/metabolism; Tuberous Sclerosis/metabolism*; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

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