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Molecular and Cellular Biology, September 2004, p. 7779-7794, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7779-7794.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Jun Blockade of Erythropoiesis: Role for Repression of GATA-1 by HERP2

Kamaleldin E. Elagib,1,{dagger} Mang Xiao,1,{dagger} Isa M. Hussaini,1 Lorrie L. Delehanty,1 Lisa A. Palmer,2 Frederick K. Racke,3 Michael J. Birrer,4 Ganapath Shanmugasundaram,5 Michael A. McDevitt,5 and Adam N. Goldfarb1*

Department of Pathology,1 Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia,2 Department of Pathology,3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,5 Molecular Mechanism Section, National Cancer Institute, Rockville, Maryland4

Received 27 January 2004/ Returned for modification 3 March 2004/ Accepted 20 May 2004

Although Jun upregulation and activation have been established as critical to oncogenesis, the relevant downstream pathways remain incompletely characterized. In this study, we found that c-Jun blocks erythroid differentiation in primary human hematopoietic progenitors and, correspondingly, that Jun factors block transcriptional activation by GATA-1, the central regulator of erythroid differentiation. Mutagenesis of c-Jun suggested that its repression of GATA-1 occurs through a transcriptional mechanism involving activation of downstream genes. We identified the hairy-enhancer-of-split-related factor HERP2 as a novel gene upregulated by c-Jun. HERP2 showed physical interaction with GATA-1 and repressed GATA-1 transcriptional activation. Furthermore, transduction of HERP2 into primary human hematopoietic progenitors inhibited erythroid differentiation. These results thus define a novel regulatory pathway linking the transcription factors c-Jun, HERP2, and GATA-1. Furthermore, these results establish a connection between the Notch signaling pathway, of which the HERP factors are a critical component, and the GATA family, which participates in programming of cellular differentiation.

* Corresponding author. Mailing address: University of Virginia School of Medicine, P.O. Box 800904, Charlottesville, VA 22908. Phone: (434) 982-0593. Fax: (434) 924-1545. E-mail: ang3x{at}virginia.edu.

{dagger} K.E.E. and M.X. contributed equally.

Molecular and Cellular Biology, September 2004, p. 7779-7794, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7779-7794.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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