Journal Article

ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether–Induced Tuberous Sclerosis Renal Cell Carcinoma

Jennifer D. Cohen, Jaime M. C. Gard, Raymond B. Nagle, Justin D. Dietrich, Terrence J. Monks and Serrine S. Lau

in Toxicological Sciences

Volume 124, issue 1, pages 75-87
Published in print November 2011 | ISSN: 1096-6080
Published online August 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr203
ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether–Induced Tuberous Sclerosis Renal Cell Carcinoma

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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-2EK/+) 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-2EK/+ 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-2EK/+ 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.

Keywords: Raf-1; phosphorylation; MAPK; renal cell carcinoma; quinol-thioether

Journal Article.  7653 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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