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J. Biol. Chem., Vol. 279, Issue 28, 29519-29527, July 9, 2004

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Positive and Negative Determinants of Target Gene Specificity in Myb Transcription Factors^*

Wanli Lei, John J. Rushton, Lisa M. Davis, Fan Liu, and Scott A. Ness

From the Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001

The A-Myb and c-Myb transcription factors share a highly conserved DNA-binding domain and activate the same promoters in reporter gene assays. However, the two proteins have distinct biological activities, and expressing them individually in human cells leads to the activation of distinct sets of endogenous genes, suggesting that each protein has a unique transcriptional specificity. Here, the structural and functional features of the Myb proteins were compared, using assays of endogenous gene expression to measure changes in specificity. When the Myb proteins were tested in different cell types, they activated unique and nearly nonoverlapping sets of genes in each cellular context. Deletion and domain swap experiments identified small, discreet positive and negative elements in A-Myb and c-Myb that were required for the regulation of specific genes, such as DHRS2, DSIPI, and mim-1. The results suggest that individual functional elements in the transcriptional activation domains are responsible for activating specific cellular genes in a context-specific manner. The results also have important implications for interpreting results from reporter gene assays, which fail to detect the differences in activity identified through endogenous gene assays, and fusion protein constructs that alter the transcriptional activation domains and the activities of the Myb proteins.

Received for publication, March 22, 2004 , and in revised form, April 19, 2004.

The microarray data are available from the NCBI data repository under GEO accession number GSE1318.

^* This work was supported by United States Public Health Service/National Cancer Institute Grant RO1 CA58443, Human Frontiers Science Program Grant RG0358/1999M, institutional support from the University of New Mexico Health Sciences Center, and Howard Hughes Medical Institute Grant 4-11347. The Affymetrix gene expression experiments were performed in the Keck-University of New Mexico Genomics Resource, a facility supported by a grant from the W. M. Keck Foundation as well as the State of New Mexico and the University of New Mexico Cancer Research and Treatment Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

Present address: Exagen Corp., 2704 Yale Blvd. SE, Albuquerque, NM.

To whom correspondence should be addressed: Dept. of Molecular Genetics and Microbiology, MSC08 4660, University of New Mexico HSC, 915 Camino de Salud NE, Albuquerque, NM 87131-0001. Tel.: 505-272-9883; E-mail: ness{at}unm.edu.

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