Regulation of surface expression of high-affinity receptors for epidermal growth factor (EGF) in hepatocytes by hormones, differentiating agents, and phorbol ester.
Freshly isolated adult rat hepatocytes exhibit a nonhomogeneous population of epidermal growth factor (EGF) receptors with about 10,000 high-affinity binding sites (Kd 20 pM) and about 200,000 low-affinity sites (Kd 600 pM) per cell. With culturing as primary monolayers under conditions where the cells show a marked increase in the sensitivity to the growth-stimulatory effect of EGF, a gradual reduction in the number of EGF receptors and an almost complete loss of high-affinity EGF receptors is seen. Insulin, which promotes growth of hepatocytes in concert with EGF, enhances the down-regulation of these high-affinity receptors. The differentiating (and growth-inhibitory) agent n-butyrate counteracts this down-regulation and preserves the high-affinity receptors. This effect of butyrate is synergistic with the glucocorticoid agent dexamethasone. Another differentiating agent, dimethylsulfoxide (DMSO), also counteracts the down-regulation of high-affinity EGF receptors. Moreover, the tumor promoter, tetradecanoylphorbol acetate (TPA), down-regulates the EGF receptor. This effect is particularly evident when studying the high-affinity receptors up-regulated by prior treatment with butyrate plus dexamethasone. Taken together these results provide strong support for the notion that an inverse relationship exists between expression of high-affinity EGF binding and responsiveness to growth activation by EGF.
Gladhaug
I P
IP
Department of Pharmacology, Faculty of Medicine, University of Oslo, Norway.
Refsnes
M
M
Christoffersen
T
T
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D003907:Dexamethasone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation
D002087:Butyrates; D020148:Butyric Acid; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D066246:ErbB Receptors; D013755:Tetradecanoylphorbol Acetate; D004121:Dimethyl Sulfoxide