P2X7 receptor stimulation upregulates Egr-1 biosynthesis involving a cytosolic Ca2+ rise, transactivation of the EGF receptor and phosphorylation of ERK and Elk-1
✍ Scribed by Luisa Stefano; Oliver G. Rössler; Désirée Griesemer; Markus Hoth; Gerald Thiel
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 328 KB
- Volume
- 213
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
The P2X~7~ receptor is an ATP‐gated ionotropic receptor that is permeable for small cations including Ca^2+^ ions. Using 293 cells expressing P2X~7~ receptors, we show that the P2X~7~ receptor‐specific ligand 2′,3′‐O‐(4‐benzoyl‐benzoyl)‐ATP (BzATP) induces a signaling cascade leading to the biosynthesis of biologically active Egr‐1, a zinc finger transcription factor. BzATP‐triggered Egr‐1 biosynthesis was attenuated by the mitogen‐activated protein kinase kinase inhibitor PD98059, by BAPTA‐AM, the acetoxymethylester of the cytosolic Ca^2+^ chelator BAPTA, and by an epidermal growth factor (EGF) receptor‐specific tyrosine kinase inhibitor (AG1478). These results indicate that phosphorylation and activation of extracellular signal‐regulated protein kinase ERK, elevated levels of intracellular Ca^2+^ and the transactivation of the EGF receptor are essential for BzATP‐induced upregulation of Egr‐1. The requirement of Ca^2+^ within the signaling cascade was upstream of Raf kinase activation. Lentiviral‐mediated expression of MAP kinase phosphatase‐1 (MKP‐1), a dual‐specific phosphatase that dephosphorylates and inactivates ERK in the nucleus, inhibited Egr‐1 biosynthesis following BzATP stimulation, indicating that MKP‐1 functions as a nuclear shut‐off device. Furthermore, the ternary complex factor Elk‐1 was phosphorylated and the transcriptional activation potential of Elk‐1 was enhanced following P2X~7~ receptor stimulation. Expression of a dominant‐negative mutant of Elk‐1 impaired BzATP‐induced upregulation of Egr‐1 biosynthesis. Thus, Elk‐1 connects the intracellular signaling cascade elicited by activation of P2X~7~ receptors with the transcription of the Egr‐1 gene. J. Cell. Physiol. 213: 36–44, 2007. © 2007 Wiley‐Liss, Inc.