This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biggs, J. R. Articles by Kraft, A. S. Search for Related Content PubMed PubMed Citation Articles by Biggs, J. R. Articles by Kraft, A. S.

---

Signaling and Regulation

Phosphorylation of AML1/RUNX1 Regulates Its Degradation and Nuclear Matrix Association

¹ Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina; ² The Scripps Research Institute, La Jolla, California; and ³ Division of Medical Oncology, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Andrew S. Kraft, Department of Medicine, P.O. Box 250955, 86 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-8284; Fax: 843-792-9456. E-mail: Kraft{at}musc.edu

The acute myeloid leukemia 1 (AML1) transcription factors are key regulators of hematopoietic differentiation. Cellular AML1c protein is found in the nucleus and can be separated into two fractions, one soluble in buffers containing salt and nonionic detergent and the other insoluble and tightly bound to the nuclear matrix. We find that the AML1c protein is modified by both phosphorylation and ubiquitination. Our studies show that the majority of the ubiquitinated AML1c is associated with the insoluble nuclear matrix. Treatment of cells with the proteasome inhibitor PS341 (Velcade, Bortezomib) increases the levels of ubiquitinated AML1c. Mutation of the four phosphorylation sites necessary for transcriptional regulation (serine 276, serine 293, serine 303, and threonine 300) mimics the effects of the proteasome inhibitor, increasing the levels of ubiquitinated, matrix-bound AML1c. We find that the soluble and insoluble forms of AML1c are degraded at a similar rate. However, mutation of these four serine/threonine residues statistically increases the half-life of the matrix-associated AML1c. Thus, phosphorylation of AML1c on specific serine/threonine residues controls both transcriptional activity and rate of degradation.

This article has been cited by other articles:

				J. A. F. Marteijn, L. T. van der Meer, L. van Emst, S. van Reijmersdal, W. Wissink, T. de Witte, J. H. Jansen, and B. A. Van der Reijden Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1 Blood, November 1, 2007; 110(9): 3128 - 3135. [Abstract] [Full Text] [PDF]

				J. R. Biggs, L. F. Peterson, Y. Zhang, A. S. Kraft, and D.-E. Zhang AML1/RUNX1 Phosphorylation by Cyclin-Dependent Kinases Regulates the Degradation of AML1/RUNX1 by the Anaphase-Promoting Complex Mol. Cell. Biol., October 15, 2006; 26(20): 7420 - 7429. [Abstract] [Full Text] [PDF]

				B. Relic, V. Benoit, N. Franchimont, M.-J. Kaiser, J.-P. Hauzeur, P. Gillet, M.-P. Merville, V. Bours, and M. G. Malaise Peroxisome Proliferator-activated Receptor-{gamma}1 Is Dephosphorylated and Degraded during BAY 11-7085-induced Synovial Fibroblast Apoptosis J. Biol. Chem., August 11, 2006; 281(32): 22597 - 22604. [Abstract] [Full Text] [PDF]