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Molecular and Cellular Biology, December 2005, p. 10205-10219, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10205-10219.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Hematopoietic Transcription Factor AML1 (RUNX1) Is Negatively Regulated by the Cell Cycle Protein Cyclin D3

Luke F. Peterson,1 Anita Boyapati,1 Velvizhi Ranganathan,1,{dagger} Atsushi Iwama,2,{ddagger} Daniel G. Tenen,2 Schickwann Tsai,3 and Dong-Er Zhang1*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037 ,1 Harvard Institutes of Medicine, Boston, Massachusetts 02115,2 Division of Hematology, University of Utah School of Medicine, Salt Lake City, Utah 841323

Received 13 November 2004/ Returned for modification 15 December 2004/ Accepted 18 July 2005

The family of cyclin D proteins plays a crucial role in the early events of the mammalian cell cycle. Recent studies have revealed the involvement of AML1 transactivation activity in promoting cell cycle progression through the induction of cyclin D proteins. This information in combination with our previous observation that a region in AML1 between amino acids 213 and 289 is important for its function led us to investigate prospective proteins associating with this region. We identified cyclin D3 by a yeast two-hybrid screen and detected AML1 interaction with the cyclin D family by both in vitro pull-down and in vivo coimmunoprecipitation assays. Furthermore, we demonstrate that cyclin D3 negatively regulates the transactivation activity of AML1 in a dose-dependent manner by competing with CBFß for AML1 association, leading to a decreased binding affinity of AML1 for its target DNA sequence. AML1 and its fusion protein AML1-ETO have been shown to shorten and prolong the mammalian cell cycle, respectively. In addition, AML1 promotes myeloid cell differentiation. Thus, our observations suggest that the direct association of cyclin D3 with AML1 functions as a putative feedback mechanism to regulate cell cycle progression and differentiation.

* Corresponding author. Mailing address: MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9581. Fax: (858) 784-9593. E-mail: dzhang{at}Scripps.edu.

{dagger} Present address: Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142.

{ddagger} Present address: The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

Molecular and Cellular Biology, December 2005, p. 10205-10219, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10205-10219.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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