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Molecular and Cellular Biology, January 2000, p. 81-90, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Auto-Inhibition of Ets-1 Is Counteracted by DNA Binding Cooperativity with Core-Binding Factor alpha 2

Tamara L. Goetz,1 Ting-Lei Gu,2 Nancy A. Speck,2 and Barbara J. Graves1,*

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550,1 and Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 037552

Received 15 June 1999/Returned for modification 22 July 1999/Accepted 4 October 1999

Auto-inhibition is a common transcriptional control mechanism that is well characterized in the regulatory transcription factor Ets-1. Autoinhibition of Ets-1 DNA binding works through an inhibitory module that exists in two conformations. DNA binding requires a change in the inhibitory module from the packed to disrupted conformation. This structural switch provides a mechanism to tightly regulate Ets-1 DNA binding. We report that the Ets-1 partner protein core-binding factor alpha 2 (CBFalpha 2; also known as AML1 or PEBP2) stimulates Ets-1 DNA binding and counteracts auto-inhibition. Support for this conclusion came from three observations. First, the level of cooperative DNA binding (10-fold) was similar to the level of repression by auto-inhibition (10- to 20-fold). Next, a region necessary for cooperative DNA binding mapped to the inhibitory module. Third, an Ets-1 mutant with a constitutively disrupted inhibitory module did not bind DNA cooperatively with CBFalpha 2. Furthermore, two additional lines of evidence indicated that CBFalpha 2 affects the structural switch by direct interactions with Ets-1. First, the retention of cooperative DNA binding on nicked duplexes eliminated a potential role of through-DNA effects. Second, cooperative DNA binding was observed on composite sites with altered spacing or reversed orientation. We suggest that only protein interactions can accommodate this observed flexibility. These findings provide a mechanism by which CBF relieves the auto-inhibition of Ets-1 and illustrates one strategy for the synergistic activity of regulatory transcription factors.

* Corresponding author. Mailing address: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550. Phone: (801) 581-7308. Fax: (801) 585-1980. E-mail: Barbara.Graves{at}hci.utah.edu.

Molecular and Cellular Biology, January 2000, p. 81-90, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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