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Molecular and Cellular Biology, September 2003, p. 6597-6608, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6597-6608.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Megakaryoblastic Leukemia 1, a Potent Transcriptional Coactivator for Serum Response Factor (SRF), Is Required for Serum Induction of SRF Target Genes

Bo Cen,1 Ahalya Selvaraj,1 Rebecca C. Burgess,1 Johann K. Hitzler,2 Zhigui Ma,3 Stephan W. Morris,3,4,5 and Ron Prywes1*

Department of Biological Sciences, Columbia University, New York, New York 10027,1 Department of Pediatrics, Division of Haematology/Oncology and Cancer and Blood, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G1X8, Canada,2 and Departments of Pathology,3 Hematology/Oncology, St. Jude Children's Research Hospital,4 Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee 381635

Received 20 March 2003/ Returned for modification 2 May 2003/ Accepted 17 June 2003

Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related transcription factor that we found strongly activated serum response element (SRE)-dependent reporter genes through its direct binding to serum response factor (SRF). The c-fos SRE is regulated by mitogen-activated protein kinase phosphorylation of ternary complex factor (TCF) but is also regulated by a RhoA-dependent pathway. The mechanism of this pathway is unclear. Since MKL1 (also known as MAL, BSAC, and MRTF-A) is broadly expressed, we assessed its role in serum induction of c-fos and other SRE-regulated genes with a dominant negative MKL1 mutant (DN-MKL1) and RNA interference (RNAi). We found that DN-MKL1 and RNAi specifically blocked SRE-dependent reporter gene activation by serum and RhoA. Complete inhibition by RNAi required the additional inhibition of the related factor MKL2 (MRTF-B), showing the redundancy of these factors. DN-MKL1 reduced the late stage of serum induction of endogenous c-fos expression, suggesting that the TCF- and RhoA-dependent pathways contribute to temporally distinct phases of c-fos expression. Furthermore, serum induction of two TCF-independent SRE target genes, SRF and vinculin, was nearly completely blocked by DN-MKL1. Finally, the RBM15-MKL1 fusion protein formed by the t(1;22) translocation of acute megakaryoblastic leukemia had a markedly increased ability to activate SRE reporter genes, suggesting that its activation of SRF target genes may contribute to leukemogenesis.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, Fairchild 813B, MC 2420, 1212 Amsterdam Avenue, New York, NY 10027. Phone: (212) 854-8281. Fax: (212) 854-7655. E-mail: mrp6{at}columbia.edu.

Molecular and Cellular Biology, September 2003, p. 6597-6608, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6597-6608.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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