Premium
An intermediary role of proHB‐EGF shedding in growth factor‐induced c‐Myc gene expression
Author(s) -
Nanba Daisuke,
Inoue Hirofumi,
Shigemi Yuka,
Shirakata Yuji,
Hashimoto Koji,
Higashiyama Shigeki
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21233
Subject(s) - epidermal growth factor , microbiology and biotechnology , receptor , growth factor , biology , fibroblast growth factor , signal transduction , heparin binding egf like growth factor , gene expression , mutant , gene , biochemistry
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.