Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 20, Issue 1, Pages 91-103Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.20.1.91-103.2000
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Funding
- NATIONAL CANCER INSTITUTE [R01CA075611, R01CA058343, R01CA090602, P30CA042014] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM038663] Funding Source: NIH RePORTER
- NCI NIH HHS [P30 CA042014, R01 CA58343, R01 CA075611, R01 CA090602, CA75611, R01 CA058343] Funding Source: Medline
- NIGMS NIH HHS [R01 GM38663, R01 GM038663] Funding Source: Medline
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Core-binding factor alpha 2 (CBF alpha 2; otherwise known as AML1 or PEBP2 alpha 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 Bunt domain in CBF alpha 2 (amino acids 51 to 178) mediates DNA binding and heterodimerization with the non-DNA-binding CBF beta subunit. Both the CBF beta subunit and the DNA-binding protein Ets-1 stimulate DNA binding by the CBF alpha 2 protein. Here we quantify and compare the extent of cooperativity between CBF alpha 2, CBF beta, and Ets-1. We also identify auto-inhibitory sequences within CBF alpha 2 and sequences that modulate its interactions with CBF beta and Ets-1. We show that sequences in the CBF alpha 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 CBF beta subunit, particularly heterodimerization off DNA. CBF beta rescinds the intramolecular inhibition of CBF alpha 2, stimulating DNA binding approximately 40-fold. In comparison, Ets-1 stimulates CBF alpha 2 DNA binding 7- to 10-fold. Although the Runt domain alone is sufficient for heterodimerization with CBF beta, 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 CBF alpha 2-CBF beta heterodimer than with CBF alpha 2 alone. These analyses demonstrate that CBF alpha 2 is subject to both negative regulation by intramolecular interactions, and positive regulation by two alternative partnerships.
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