Acute effects of interferon on estrogen receptor function do not involve the extracellular signal-regulated kinases p42(mapk) and p44(mapk)

Exposure to type I interferons (IFN) increased estrogen receptor (ER) ligan d binding and induced protein kinase C (PKC) translocation within 30 min bu t had no effect on net incorporation of [(32)p] info ER in Madin Darby bovi ne kidney (MDBK) cells. Ligand binding was also increased within 30 min by phorbol ester and the protein phosphatase inhibitor okadaic acid. Mitogen-a ctivated protein (MAP) kinase phosphorylation was initially inhibited betwe en 2 and 30 min and subsequently activated between 30 and 60 min after trea tment with IFN. The activatory response was blocked by the PKC inhibitor Ro 31-8220. Following transient transfection with an ERE-CAT reporter constru ct, IFN increased CAT expression after 6 h but decreased ER ligand binding, transcriptional activity and phosphorylation after 48 h, probably as a res ult of decreased ER concentrations, The results rule out rapid activation o f ER ligand binding through phosphorylation at Ser(118) by MAP kinase becau se (1) the increase in ligand binding preceded activation of MAP kinase, an d (2) IFN had no short-term effect on [P-32]incorporation or ER transcripti onal activity. The rapid effect of LFN on ER ligand binding is postulated t o reflect phosphorylation of the receptor at Tyr(537) by p56(lck), a member of the Src family of PKC-activated tyrosine kinases.