ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether-induced tuberous sclerosis renal cell carcinoma.

Abstract

The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase signaling cascades have been implicated in a number of human cancers. The tumor suppressor gene tuberous sclerosis-2 (Tsc-2) functions as a negative regulator of mTOR. Critical proteins in both pathways are activated following treatment of Eker rats (Tsc-2(EK/+)) with the nephrocarcinogen 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ), which also results in loss of the wild-type allele of Tsc-2 in renal preneoplastic lesions and tumors. Western blot analysis of kidney tumors formed following treatment of Tsc-2(EK/+) rats with TGHQ for 8 months revealed increases in B-Raf, Raf-1, pERK, cyclin D1, 4EBP1, and p-4EBP1-Ser65, -Thr70, and -Thr37/46 expression. Similar changes are observed following TGHQ-mediated transformation of primary renal epithelial cells derived from Tsc-2(EK/+) rats (quinol-thioether rat renal epithelial [QTRRE] cells) that are also null for tuberin. These cells exhibit high ERK, B-Raf, and Raf-1 kinase activity and increased expression of all p-4EBP1s and cyclin D1. Treatment of the QTRRE cells with the Raf kinase inhibitor, sorafenib, or the MEK1/2 kinase inhibitor, PD 98059, produced a significant decrease in the protein expression of all p-4EBP1s and cyclin D1. Following siRNA knockdown of Raf-1, Western blot analysis revealed a significant decrease in Raf-1, cyclin D1, and all p-4EBP1 forms noted above. In contrast, siRNA knockdown of B-Raf resulted in a nominal change in these proteins. The data indicate that Raf-1/MEK/ERK participates in crosstalk with 4EBP1, which represents a novel pathway interaction leading to increased protein synthesis, cell growth, and kidney tumor formation.

• Authors: Jennifer D Cohen, Jaime M C Gard, Raymond B Nagle, Justin D Dietrich, Terrence J Monks, Serrine S Lau
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 124 Issue 1 Pg. 75-87 (Nov 2011) ISSN: 1096-0929 [Electronic] United States
• PMID: 21813464 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• Ccnd1 protein, rat
• Eif4ebp1 protein, rat
• Hydroquinones
• Intracellular Signaling Peptides and Proteins
• Phosphoproteins
• RNA, Small Interfering
• TSC2 protein, human
• Tsc2 protein, rat
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• 2,3,5-(triglutathion-S-yl)hydroquinone
• Cyclin D1
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Raf1 protein, rat
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase Kinases
• Glutathione

Topics

• Animals
• Carcinoma, Renal Cell (chemically induced, genetics, metabolism, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Culture Techniques
• Cell Line
• Cell Transformation, Neoplastic (drug effects, genetics, metabolism)
• Cyclin D1 (biosynthesis, genetics)
• Epithelial Cells (drug effects, metabolism)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Glutathione (analogs & derivatives, toxicity)
• Humans
• Hydroquinones (toxicity)
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins
• Kidney Neoplasms (chemically induced, genetics, metabolism, pathology)
• Loss of Heterozygosity
• MAP Kinase Kinase Kinases (genetics, metabolism)
• Male
• Phosphoproteins (genetics, metabolism)
• Protein Biosynthesis
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Proto-Oncogene Proteins c-raf
• RNA, Small Interfering (genetics)
• Rats
• Rats, Mutant Strains
• Receptor Cross-Talk (drug effects)
• Signal Transduction
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (biosynthesis, genetics)