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Molecular and Cellular Biology, January 1999, p. 155-163, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Novel Intron Element Operates Posttranscriptionally To Regulate Human N-myc Expression

Louise E. Sivak,1 Geneviève Pont-Kingdon,2 Kim Le,2 Gabriele Mayr,2 Kuei-Fang Tai,2 Ben T. Stevens,2 and William L. Carroll1,2,3,4,*

Department of Experimental Pathology,1 Center for Children of the Huntsman Cancer Institute,2 Program in Human Molecular Biology and Genetics,3 and Division of Pediatric Hematology/Oncology, Department of Pediatrics,4 University of Utah School of Medicine, Salt Lake City, Utah 84112

Received 3 June 1998/Returned for modification 31 August 1998/Accepted 23 September 1998

Precisely regulated expression of oncogenes and tumor suppressor genes is essential for normal development, and deregulated expression can lead to cancer. The human N-myc gene normally is expressed in only a subset of fetal epithelial tissues, and its expression is extinguished in all adult tissues except transiently in pre-B lymphocytes. The N-myc gene is overexpressed due to genomic amplification in the childhood tumor neuroblastoma. In previous work to investigate mechanisms of regulation of human N-myc gene expression, we observed that N-myc promoter-chloramphemicol acelyltransferase reporter constructs containing sequences 5' to exon 1 were active in all cell types examined, regardless of whether endogenous N-myc RNA was detected. In contrast, inclusion of the first exon and a portion of the first intron allowed expression only in those cell types with detectable endogenous N-myc transcripts. We investigated further the mechanisms by which this tissue-specific control of N-myc expression is achieved. Using nuclear run-on analyses, we determined that the N-myc gene is actively transcribed in all cell types examined, indicating a posttranscriptional mode of regulation. Using a series of N-myc intron 1 deletion constructs, we localized a 116-bp element (tissue-specific element [TSE]) within the first intron that directs tissue-specific N-myc expression. The TSE can function independently to regulate expression of a heterologous promoter-reporter minigene in a cell-specific pattern that mirrors the expression pattern of the endogenous N-myc gene. Surprisingly, the TSE can function in both sense and antisense orientations to regulate gene expression. Our data indicate that the human N-myc TSE functions through a posttranscriptional mechanism to regulate N-myc expression.

* Corresponding author. Mailing address: Center for Children of the Huntsman Cancer Institute, Eccles Institute of Human Genetics, Bldg. 533, Room 3240, University of Utah, Salt Lake City, UT 84112. Phone: (801) 585-5004. Fax: (801) 585-3501. E-mail: bill.carroll{at}hci.utah.edu.

Molecular and Cellular Biology, January 1999, p. 155-163, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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