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Molecular and Cellular Biology, January 2000, p. 91-103, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Auto-Inhibition and Partner Proteins, Core-Binding Factor beta  (CBFbeta ) and Ets-1, Modulate DNA Binding by CBFalpha 2 (AML1)

Ting-Lei Gu,1 Tamara L. Goetz,2 Barbara J. Graves,2 and Nancy A. Speck1,*

Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755,1 and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-55502

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

Core-binding factor alpha 2 (CBFalpha 2; otherwise known as AML1 or PEBP2alpha B) is a DNA-binding subunit in the family of core-binding factors (CBFs), heterodimeric transcription factors that play pivotal roles in multiple developmental processes in mammals, including hematopoiesis and bone development. The Runt domain in CBFalpha 2 (amino acids 51 to 178) mediates DNA binding and heterodimerization with the non-DNA-binding CBFbeta subunit. Both the CBFbeta subunit and the DNA-binding protein Ets-1 stimulate DNA binding by the CBFalpha 2 protein. Here we quantify and compare the extent of cooperativity between CBFalpha 2, CBFbeta , and Ets-1. We also identify auto-inhibitory sequences within CBFalpha 2 and sequences that modulate its interactions with CBFbeta and Ets-1. We show that sequences in the CBFalpha 2 Runt domain and sequences C terminal to amino acid 214 inhibit DNA binding. Sequences C terminal to amino acid 214 also inhibit heterodimerization with the non-DNA-binding CBFbeta subunit, particularly heterodimerization off DNA. CBFbeta rescinds the intramolecular inhibition of CBFalpha 2, stimulating DNA binding approximately 40-fold. In comparison, Ets-1 stimulates CBFalpha 2 DNA binding 7- to 10-fold. Although the Runt domain alone is sufficient for heterodimerization with CBFbeta , sequences N terminal to amino acid 41 and between amino acids 190 and 214 are required for cooperative DNA binding with Ets-1. Cooperative DNA binding with Ets-1 is less pronounced with the CBFalpha 2-CBFbeta heterodimer than with CBFalpha 2 alone. These analyses demonstrate that CBFalpha 2 is subject to both negative regulation by intramolecular interactions, and positive regulation by two alternative partnerships.

* Corresponding author. Mailing address: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755. Phone: (603) 650-1159. Fax: (603) 650-1128. E-mail: Nancy.Speck{at}dartmouth.edu.

Molecular and Cellular Biology, January 2000, p. 91-103, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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