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J. Biol. Chem., Vol. 279, Issue 15, 15678-15687, April 9, 2004

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AML1/RUNX1 Increases During G₁ to S Cell Cycle Progression Independent of Cytokine-dependent Phosphorylation and Induces Cyclin D3 Gene Expression^*

Florence Bernardin-Fried, Tanawan Kummalue, Suzanne Leijen, Michael I. Collector, Katya Ravid, and Alan D. Friedman¶

From the Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland 21231 and the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02128

AML1/RUNX1, a member of the core binding factor (CBF) family stimulates myelopoiesis and lymphopoiesis by activating lineage-specific genes. In addition, AML1 induces S phase entry in 32Dcl3 myeloid or Ba/F3 lymphoid cells via transactivation. We now found that AML1 levels are regulated during the cell cycle. 32Dcl3 and Ba/F3 cell cycle fractions were prepared using elutriation. Western blotting and a gel shift/supershift assay demonstrated that endogenous CBF DNA binding and AML1 levels were increased 2-4-fold in S and G₂/M phase cells compared with G₁ cells. In addition, G₁ arrest induced by mimosine reduced AML1 protein levels. In contrast, AML1 RNA did not vary during cell cycle progression relative to actin RNA. Analysis of exogenous Myc-AML1 or AML1-ER demonstrated a significant reduction in G₁ phase cells, whereas levels of exogenous DNA binding domain alone were constant, lending support to the conclusion that regulation of AML1 protein stability contributes to cell cycle variation in endogenous AML1. However, cytokine-dependent AML1 phosphorylation was independent of cell cycle phase, and an AML1 mutant lacking two ERK phosphorylation sites was still cell cycle-regulated. Inhibition of AML1 activity with the CBF-SMMHC or AML1-ETO oncoproteins reduced cyclin D3 RNA expression, and AML1 bound and activated the cyclin D3 promoter. Signals stimulating G₁ to S cell cycle progression or entry into the cell cycle in immature hematopoietic cells might do so in part by inducing AML1 expression, and mutations altering pathways regulating variation in AML1 stability potentially contribute to leukemic transformation.

Received for publication, September 9, 2003 , and in revised form, December 31, 2003.

^* This work was supported by National Institutes of Health Grant CA098805 and the Children's Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Leukemia Society Scholar. To whom correspondence should be addressed: Johns Hopkins University, CRB 253; 1650 Orleans St., Baltimore, MD 21231. Tel.: 410-955-2095; Fax: 410-955-8897; E-mail: afriedm2{at}jhmi.edu.

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