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Molecular and Cellular Biology, July 1999, p. 4788-4797, Vol. 19, No. 7
0270-7306/99/$04.00+0

Upstream Stimulatory Factor Regulates Major Histocompatibility Complex Class I Gene Expression: the U2Delta E4 Splice Variant Abrogates E-Box Activity

T. Kevin Howcroft,1,* Charles Murphy,1 Jocelyn D. Weissman,1 Sam J. Huber,1 Michèle Sawadogo,2 and Dinah S. Singer1

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360,1 and Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 770302

Received 11 February 1999/Returned for modification 24 March 1999/Accepted 19 April 1999

The tissue-specific expression of major histocompatibility complex class I genes is determined by a series of upstream regulatory elements, many of which remain ill defined. We now report that a distal E-box element, located between bp -309 and -314 upstream of transcription initiation, acts as a cell type-specific enhancer of class I promoter activity. The class I E box is very active in a neuroblastoma cell line, CHP-126, but is relatively inactive in the HeLa epithelial cell line. The basic helix-loop-helix leucine zipper proteins upstream stimulatory factor 1 (USF1) and USF2 were shown to specifically recognize the class I E box, resulting in the activation of the downstream promoter. Fine mapping of USF1 and USF2 amino-terminal functional domains revealed differences in their abilities to activate the class I E box. Whereas USF1 contained only an extended activation domain, USF2 contained both an activation domain and a negative regulatory region. Surprisingly, the naturally occurring splice variant of USF2 lacking the exon 4 domain, U2Delta E4, acted as a dominant-negative regulator of USF-mediated activation of the class I promoter. This latter activity is in sharp contrast to the known ability of U2Delta E4 to activate the adenovirus major late promoter. Class I E-box function is correlated with the relative amount of U2Delta E4 in a cell, leading to the proposal that U2Delta E4 modulates class I E-box activity and may represent one mechanism to fine-tune class I expression in various tissues.

* Corresponding author. Mailing address: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 4B-17, 10 Center Dr. MSC 1360, Bethesda, MD 20892-1360. Phone: (301) 496-9097. Fax: (301) 480-8499. E-mail: Howcrofk{at}Exchange.nih.gov.

Molecular and Cellular Biology, July 1999, p. 4788-4797, Vol. 19, No. 7
0270-7306/99/$04.00+0


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