Up-regulation of CAR expression through Elk-1 in HepG2 and SW480 cells by serum starvation stress

Osabe, Makoto; Sugatani, Junko; Takemura, Akiko; Kurosawa, Masatoshi; Yamazaki, Yasuhiro; Ikari, Akira; Miwa, Masao

doi:10.1016/j.febslet.2009.01.051

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Volume 583, Issue 5 , Pages 885-889, 4 March 2009

Up-regulation of CAR expression through Elk-1 in HepG2 and SW480 cells by serum starvation stress

Edited by Robert Barouki

Makoto Osabe
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Junko Sugatani
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
- Global Center of Excellence for Innovation in Human Health Sciences, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan
- Corresponding author. Address: Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Fax: +81 54 264 5773.
Akiko Takemura
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Masatoshi Kurosawa
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Yasuhiro Yamazaki
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Akira Ikari
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Masao Miwa
- Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

Received 3 November 2008; received in revised form 6 January 2009; accepted 31 January 2009. published online 06 February 2009.

Abstract

Constitutive androstane receptor (CAR) is a transcription factor regulating the expression of several genes related to drug metabolism. CAR expression was elevated in human HepG2 and SW480 cells by serum starvation. From reporter gene assays, mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we identified the serum response element at −142/−139 in the CAR gene transactivated by Elk-1. Whereas treatment with U0126 (ERK inhibitor) enhanced CAR expression, SP600125 (stress-activated protein kinase inhibitor, SAPK) suppressed the phosphorylation of Elk-1 caused by serum-starvation stress and the elevation of CAR mRNA, suggesting that CAR expression may be mediated by phosphorylated Elk-1 via the SAPK signaling pathway.

Keywords: Constitutive androstane receptor, Serum starvation, Elk-1, SP600125, HepG2 cell, SW480 cell

Abbreviations: AhR, aryl hydrocarbon receptor, CAR, constitutive androstane receptor, DMEM, Dulbecco’s modified Eagle’s medium, FCS, fetal calf serum, HNF4α, hepatocyte nuclear factor 4α, PXR, pregnane X receptor, RXR, retinoid X receptor, SAPK, stress-activated protein kinase, siRNA, short interfering RNA, SRE, serum response element