An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression.
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.
Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.
Daisuke
D
Nanba
Hirofumi
H
Inoue
Yuka
Y
Shigemi
Yuji
Y
Shirakata
Koji
K
Hashimoto
Shigeki
S
Higashiyama
D000256:Adenoviridae / Q000235:genetics; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology; D005347:Fibroblasts; D005354:Fibrosarcoma / Q000473:pathology; D015870:Gene Expression; D016259:Genes, myc; D006493:Heparin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D011401:Promoter Regions, Genetic; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D006493:Heparin; D066246:ErbB Receptors; D000469:Alkaline Phosphatase