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PMID: 12944485 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.

Molecular and cellular biology ·Vol. 23 ·No. 18 ·2003-09-00 ·Pages 6597-608

Cen B, Selvaraj A, Burgess RC, Hitzler JK, Ma Z, Morris SW, Prywes R

Abstract

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.

MeSH Terms
Animals Cells, Cultured DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation/drug effects Genes, Dominant Genes, Reporter Genes, fos Humans Mice Oncogene Proteins, Fusion/genetics,metabolism,pharmacology Protein Structure, Tertiary RNA Interference RNA-Binding Proteins/genetics,metabolism Serum Response Element Serum Response Factor/genetics,metabolism Trans-Activators Transcription Factors/genetics,metabolism Transcriptional Activation/drug effects rhoA GTP-Binding Protein/genetics,metabolism
Chemicals
DNA-Binding Proteins MRTFA protein, human MRTFB protein, human Oncogene Proteins, Fusion RBM15 protein, human RNA-Binding Proteins Serum Response Factor Trans-Activators Transcription Factors p62TCF protein, human p62TCF protein, mouse rhoA GTP-Binding Protein
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Cen Bo
Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
Selvaraj Ahalya
Burgess Rebecca C
Hitzler Johann K
Ma Zhigui
Morris Stephan W
Prywes Ron
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.18.6597-6608.2003
Published
2003-09-00
Pages
6597-608
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC193697
Subset
IM
Grants
NCI NIH HHS · R01 CA050329 · United States
NCI NIH HHS · CA 50329 · United States
NCI NIH HHS · CA 87064 · United States
NCI NIH HHS · P30 CA021765 · United States
NCI NIH HHS · R01 CA087064 · United States
NCI NIH HHS · CA 21765 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.18.6597-6608.2003 PMC Full Text View journal details
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