Induction of autocrine epidermal growth factor receptor ligands in human keratinocytes by insulin/insulin-like growth factor-1.
Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory mechanism involved in epithelial homeostasis, and, possibly, hyperproliferative diseases. Insulin-like growth factor (IGF)-1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinocytes in situ. In this report, we demonstrate that IGF-1/insulin induced production of keratinocyte-derived autocrine growth factors that bind to the EGF receptor. Increased steady-state mRNA levels for transforming growth factor alpha (TGF-alpha) and for amphiregulin (AR) were observed upon incubation of keratinocytes with mitogenic concentrations of IGF-1. IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF-1 on cultured keratinocytes. These results suggest that stimulation of keratinocyte growth of IGF-1 requires activation of an EGF receptor-mediated autocrine loop.
Vardy
D A
DA
Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104, USA.
Kari
C
C
Lazarus
G S
GS
Jensen
P J
PJ
Zilberstein
A
A
Plowman
G D
GD
Rodeck
U
U
D066258:Amphiregulin; D000906:Antibodies / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D016211:Transforming Growth Factor alpha / Q000378:metabolism
C587848:AREG protein, human; D066258:Amphiregulin; D000906:Antibodies; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016211:Transforming Growth Factor alpha; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors