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Molecular and Cellular Biology, October 2006, p. 7420-7429, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00597-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

AML1/RUNX1 Phosphorylation by Cyclin-Dependent Kinases Regulates the Degradation of AML1/RUNX1 by the Anaphase-Promoting Complex{ddagger}

Joseph R. Biggs,1,{dagger} Luke F. Peterson,1,{dagger} Youhong Zhang,2 Andrew S. Kraft,2 and Dong-Er Zhang1*

Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,1 Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, South Carolina 294252

Received 6 April 2006/ Returned for modification 10 May 2006/ Accepted 25 July 2006

AML1 (RUNX1) regulates hematopoiesis, angiogenesis, muscle function, and neurogenesis. Previous studies have shown that phosphorylation of AML1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of AML1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (CDKs) Cdk1 and Cdk2. Furthermore, these residues can be phosphorylated in vitro by purified Cdk1/cyclin B and Cdk2/cyclin A. Mutant AML1 protein which cannot be phosphorylated at these sites (AML1-4A) is more stable than wild-type AML1. AML-4A is resistant to degradation mediated by Cdc20, one of the substrate-targeting subunits of the anaphase-promoting complex (APC). However, Cdh1, another targeting subunit used by the APC, can mediate the degradation of AML1-4A. A phospho-mimic protein, AML1-4D, can be targeted by Cdc20 or Cdh1. These observations suggest that both Cdc20 and Cdh1 can target AML1 for degradation by the APC but that AML1 phosphorylation may affect degradation mediated by Cdc20-APC to a greater degree.

* Corresponding author. Mailing address: The Scripps Research Institute, 10550 North Torrey Pines Rd., MEM-L51, La Jolla, CA 92037. Phone: (858) 784-9558. Fax: (858) 784-9593. E-mail: dzhang{at}scripps.edu.

{ddagger} This is paper number 17930-MEM from The Scripps Research Institute.

{dagger} J.R.B. and L.F.P. contributed equally to this work.

Molecular and Cellular Biology, October 2006, p. 7420-7429, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00597-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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