title: The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3.
abstract: 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 CBFbeta 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.
authors.affiliation: Dept. of Molecular Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Luke F
authors.initials: LF
authors.lastname: Peterson
authors.forename: Anita
authors.initials: A
authors.lastname: Boyapati
authors.forename: Velvizhi
authors.initials: V
authors.lastname: Ranganathan
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Schickwann
authors.initials: S
authors.lastname: Tsai
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C534696:CCND3 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D056743:Cyclin D3; D016213:Cyclins; D004247:DNA; D006655:Histone Deacetylases