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Molecular and Cellular Biology, April 2001, p. 2249-2258, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2249-2258.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

MLL and CREB Bind Cooperatively to the Nuclear Coactivator CREB-Binding Protein

Patricia Ernst,1 Jing Wang,1 Mary Huang,2 Richard H. Goodman,2 and Stanley J. Korsmeyer1,*

Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115,1 and Vollum Institute, Oregon Health Sciences University, Portland, Oregon 972012

Received 30 June 2000/Returned for modification 10 August 2000/Accepted 10 January 2001

A fragment of the mixed-lineage leukemia (MLL) gene (Mll, HRX, ALL-1) was identified in a yeast genetic screen designed to isolate proteins that interact with the CREB-CREB-binding protein (CBP) complex. When tested for binding to CREB or CBP individually, this MLL fragment interacted directly with CBP, but not with CREB. In vitro binding experiments refined the minimal region of interaction to amino acids 2829 to 2883 of MLL, a potent transcriptional activation domain, and amino acids 581 to 687 of CBP (the CREB-binding or KIX domain). The transactivation activity of MLL was dependent on CBP, as either adenovirus E1A expression, which inhibits CBP activity, or alteration of MLL residues important for CBP interaction proved effective at inhibiting MLL-mediated transactivation. Single amino acid substitutions within the MLL activation domain revealed that five hydrophobic residues, potentially forming a hydrophobic face of an amphipathic helix, were critical for the interaction of MLL with CBP. Using purified components, we found that the MLL activation domain facilitated the binding of CBP to phosphorylated CREB. In contrast with paradigms in which factors compete for limiting quantities of CBP, these results reveal that two distinct transcription factor activation domains can cooperatively target the same motif on CBP.

* Corresponding author. Mailing address: Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, One Jimmy Fund Way, SM-758, Boston, MA 02115. Phone: (617) 632-6402. Fax: (617) 632-6401. E-mail: stanley_korsmeyer{at}dfci.harvard.edu.

Molecular and Cellular Biology, April 2001, p. 2249-2258, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2249-2258.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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