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

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.

• Authors: Jennifer D Cohen, Kimberly Y Tham, Nicholas J Mastrandrea, Alfred C Gallegos, Terrence J Monks, Serrine S Lau
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 122 Issue 2 Pg. 361-71 (Aug 2011) ISSN: 1096-0929 [Electronic] United States
• PMID: 21693435 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzenesulfonates
• Ccnd1 protein, rat
• Cdkn1b protein, rat
• Hydroquinones
• Phenylurea Compounds
• Phosphodiesterase Inhibitors
• Pyridines
• RNA, Small Interfering
• TSC2 protein, human
• Tsc2 protein, mouse
• Tsc2 protein, rat
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• 2,3,5-(triglutathion-S-yl)hydroquinone
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p27
• Niacinamide
• Bucladesine
• Sorafenib
• Theophylline
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinases
• Glutathione
• Pentoxifylline

Topics

• Animals
• Benzenesulfonates (metabolism)
• Bucladesine (pharmacology)
• Carcinoma, Renal Cell (chemically induced)
• Cell Line
• Cyclin D1 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (antagonists & inhibitors, genetics, metabolism)
• Cytosol (metabolism)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Glutathione (analogs & derivatives, pharmacology)
• Humans
• Hydroquinones (pharmacology)
• Kidney Neoplasms (chemically induced)
• Male
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Niacinamide (analogs & derivatives)
• Pentoxifylline (metabolism)
• Phenylurea Compounds
• Phosphodiesterase Inhibitors (metabolism)
• Proto-Oncogene Proteins B-raf (metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Pyridines (metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Signal Transduction
• Sorafenib
• Theophylline (metabolism)
• Tuberous Sclerosis (metabolism)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (genetics, metabolism)