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Upstream Stimulatory Factor Regulates Constitutive Expression and Hormonal Suppression of the 90K (Mac-2BP) Protein

Cell Regulation Section (A.G., B.F., M.N., H.-K.C., C.G., G.N., L.D.K.), Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and Experimental Immunology Branch (T.K.H., D.S.S.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; University "G. D’Annunzio" Foundation (A.G., N.T., B.F., C.G., G.N., S.I.), 66100 Chieti, Italy; and Edison Biotechnology Institute (L.D.K.), Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio 45701

Address all correspondence and requests for reprints to: Antonino Grassadonia, M.D., Ph.D., Dipartimento di Oncologia e Neuroscienze, Sezione di Oncologia Medica, Centro Servizi Biomedici (SEBI), via dei Vestini, 66100 Chieti, Italy. E-mail: grassadonia{at}unich.it.

We previously reported that hormones important for the normal growth and function of FRTL-5 rat thyroid cells, TSH, or its cAMP signal plus insulin or IGF-I, could transcriptionally suppress constitutive and -interferon (IFN)-increased synthesis of the 90K protein (also known as Mac-2BP). Here we cloned the 5'-flanking region of the rat 90K gene and identified a minimal promoter containing an interferon response element and a consensus E-box or upstream stimulator factor (USF) binding site, which are highly conserved in both the human and murine genes. We show that suppression of constitutive and -IFN-increased 90K gene expression by TSH/cAMP plus insulin/IGF-I depends on the ability of the hormones to decrease the binding of USF to the E-box, located upstream of the interferon response element. This site is required for the constitutive expression of the 90K gene. Transfection with USF1 and USF2 cDNAs increases constitutive promoter activity, attenuates the ability of TSH/cAMP plus insulin/IGF-I to decrease constitutive or -IFN-increased 90K gene expression but does not abrogate the ability of -IFN itself to increase 90K gene expression.