An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression
✍ Scribed by Daisuke Nanba; Hirofumi Inoue; Yuka Shigemi; Yuji Shirakata; Koji Hashimoto; Shigeki Higashiyama
- Book ID
- 102313361
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 414 KB
- Volume
- 214
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Activation of growth factor receptors by ligand binding leads to an increased expression of c‐Myc, a transcriptional regulator for cell proliferation. The activation of transcriptional factors via the activated receptors is thought to be the main role of c‐Myc gene expression. We demonstrate here that epidermal growth factor receptor (EGFR)‐ and fibroblast growth factor receptor (FGFR)‐mediated__c‐Myc__ induction and cell cycle progression in primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin‐binding EGF‐like growth factor (Hb‐egf) gene, or by a metalloproteinase inhibitor, although molecules downstream of the receptors are activated. Induction of c‐Myc expression by EGF or basic FGF is recovered in Hb‐egf‐depleted MEFs by overexpression of wild‐type proHB‐EGF, but no recovery was observed with an uncleavable mutant of proHB‐EGF. The uncleavable mutant also inhibited EGF‐induced acetylation of histone H3 at the mouse c‐Myc first intron region, which could negatively affect transcriptional activation. We conclude that signal transduction initiated by generation of the carboxyl‐terminal fragment of proHB‐EGF (HB‐EGF‐CTF) in the shedding event plays an important intermediary role between growth factor receptor activation and c‐Myc gene induction. J. Cell. Physiol. 214: 465–473, 2008. © 2007 Wiley‐Liss, Inc.