Auto-Inhibition and Partner Proteins, Core-Binding Factor β (CBFβ) and Ets-1, Modulate DNA Binding by CBFα2 (AML1)

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Published inMolecular and Cellular Biology Vol. 20; no. 1; pp. 91 - 103
Main Authors Gu, Ting-Lei, Goetz, Tamara L., Graves, Barbara J., Speck, Nancy A.
Format Journal Article
LanguageEnglish
Published American Society for Microbiology 01.01.2000
Taylor & Francis
Subjects
Transcriptional Regulation
Online AccessGet full text
ISSN0270-7306
1098-5549
1098-5549
DOI10.1128/MCB.20.1.91-103.2000

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Core-binding factor α2 (CBFα2; otherwise known as AML1 or PEBP2αB) 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 CBFα2 (amino acids 51 to 178) mediates DNA binding and heterodimerization with the non-DNA-binding CBFβ subunit. Both the CBFβ subunit and the DNA-binding protein Ets-1 stimulate DNA binding by the CBFα2 protein. Here we quantify and compare the extent of cooperativity between CBFα2, CBFβ, and Ets-1. We also identify auto-inhibitory sequences within CBFα2 and sequences that modulate its interactions with CBFβ and Ets-1. We show that sequences in the CBFα2 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 CBFβ subunit, particularly heterodimerization off DNA. CBFβ rescinds the intramolecular inhibition of CBFα2, stimulating DNA binding approximately 40-fold. In comparison, Ets-1 stimulates CBFα2 DNA binding 7- to 10-fold. Although the Runt domain alone is sufficient for heterodimerization with CBFβ, 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 CBFα2-CBFβ heterodimer than with CBFα2 alone. These analyses demonstrate that CBFα2 is subject to both negative regulation by intramolecular interactions, and positive regulation by two alternative partnerships.
Author Nancy A. Speck
Barbara J. Graves
Ting-Lei Gu
Tamara L. Goetz
AuthorAffiliation Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, 1 and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550 2
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  givenname: Ting-Lei
  surname: Gu
  fullname: Gu, Ting-Lei
  organization: Department of Biochemistry, Dartmouth Medical School
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  givenname: Tamara L.
  surname: Goetz
  fullname: Goetz, Tamara L.
  organization: Huntsman Cancer Institute, University of Utah
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  surname: Speck
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  email: Nancy.Speck@dartmouth.edu
  organization: Department of Biochemistry, Dartmouth Medical School
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Notes 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@dartmouth.edu.
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Core-binding factor α2 (CBFα2; otherwise known as AML1 or PEBP2αB) is a DNA-binding subunit in the family of core-binding factors (CBFs), heterodimeric...
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SubjectTerms Transcriptional Regulation
Title Auto-Inhibition and Partner Proteins, Core-Binding Factor β (CBFβ) and Ets-1, Modulate DNA Binding by CBFα2 (AML1)
URI http://mcb.asm.org/content/20/1/91.abstract
https://www.tandfonline.com/doi/abs/10.1128/MCB.20.1.91-103.2000
https://pubmed.ncbi.nlm.nih.gov/PMC85059
Volume 20
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