cAMP-dependent cytosolic mislocalization of p27 kip-Cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma

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

Research output: Contribution to journalArticle

8 Scopus citations

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-Syl) 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 TGHQtransformed 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/ cyclinD1 protein levels inQTRREcells. 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 cyclinD1 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.

Original languageEnglish (US)
Pages (from-to)361-371
Number of pages11
JournalToxicological Sciences
Volume122
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • B-raf
  • Cyclin D1
  • Quinol-thioether
  • Renal cell carcinoma
  • cAMP
  • p27

ASJC Scopus subject areas

  • Toxicology

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