Differential effects of ethanol on insulin-like growth factor-I receptor signaling.
BACKGROUND
Activation of the insulin-like growth factor I receptor (IGF-IR) by its ligands IGF-I and IGF-II induces cell proliferation and protects against apoptosis. Ethanol inhibits IGF-IR tyrosine autophosphorylation, which subsequently interferes with the activation of key downstream signaling mediators including insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and mitogen-activated protein (MAP) kinase. The ethanol-induced inhibition of IGF-IR signaling reduces mitogenesis and enhances apoptosis. In the current study, we demonstrate that the antiproliferative action of ethanol can be modulated by differential sensitivity of the autophosphorylation of the IGF-IR to ethanol.


METHODS
A series of subclones was generated from 3T3 cells that express the human IGF-IR.


RESULTS
There was considerable variability in the ability of ethanol to inhibit IGF-I-dependent IGF-IR tyrosine autophosphorylation and MAP kinase activation, despite equivalent IGF-IR expression. The IGF-IR was completely resistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF-IR autophosphorylation to ethanol correlated directly with the inhibition of IGF-I-mediated MAP kinase activation and cell proliferation. Resistant subclones exhibited features of the transformed phenotype including high MAP kinase activity, partial loss of contact inhibition, and the development of foci at confluency. The IGF-IR isolated from ethanol-resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro, whereas ethanol inhibited the autophosphorylation of IGF-IR obtained from sensitive cells.


CONCLUSIONS
Our findings are the first to demonstrate the modulation of ethanol sensitivity of a tyrosine kinase receptor, and they provide a molecular basis for differential effects of ethanol on cell proliferation.
Seiler
A E
AE
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Ross
B N
BN
Green
J S
JS
Rubin
R
R
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002642:Chick Embryo; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism
D002492:Central Nervous System Depressants; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1