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, Serrine S. Lau

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Article numberkfr203
Pages (from-to)75-87
Number of pages13
JournalToxicological Sciences
Volume124
Issue number1
DOIs
StatePublished - Nov 1 2011

Keywords

  • MAPK
  • Phosphorylation
  • Quinol-thioether
  • Raf-1
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Toxicology

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