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J. Biol. Chem., Vol. 282, Issue 9, 6473-6483, March 2, 2007

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The Transcriptional Repressor GFI-1 Antagonizes PU.1 Activity through Protein-Protein Interaction^*

Richard Dahl, Supported by American Cancer Society Research Scholar Grant RSG-06-170-01-LIB. Junior Faculty Scholar of the American Society of Hematology^¶1, Sangeeta R. Iyer^¶, Kristin S. Owens, Dorothy D. Cuylear², and M. Celeste Simon^¶3

From the Department of Internal Medicine, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131, the Howard Hughes Medical Institute, and the ^¶Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Mice lacking the zinc finger transcriptional repressor protein GFI-1 are neutropenic. These mice generate abnormal immature myeloid cells exhibiting characteristics of both macrophages and granulocytes. Furthermore, Gfi-1^-/- mice are highly susceptible to bacterial infection. Interestingly, Gfi-1^-/- myeloid cells overexpress target genes of the PU.1 transcription factor such as the macrophage colony-stimulating factor receptor and PU.1 itself. We therefore determined whether GFI-1 modulates the transcriptional activity of PU.1. Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. Retroviral expression of GFI-1 in primary murine hematopoietic progenitors increased granulocyte differentiation at the expense of macrophage differentiation. We interbred Gfi-1^+/- and PU.1^+/- mice and observed that heterozygosity at the PU.1 locus partially rescued the Gfi-1^-/- mixed myeloid lineage phenotype, but failed to restore granulocyte differentiation. Our data demonstrate that GFI-1 represses PU.1 activity and that lack of this repression in Gfi-1^-/- myeloid cells contributes to the observed mixed lineage phenotype.

Received for publication, August 9, 2006 , and in revised form, December 21, 2006.

^* This work was supported in part by the Abramson Family Cancer Research Institute, the Howard Hughes Medical Institute, the Leukemia Research Foundation, and the dedicated health research funds of the University of New Mexico School of Medicine. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

² Supported in part by Institutional National Research Service Award T32HL076595 from the National Institutes of Health.

³ Investigator of the Howard Hughes Medical Institute.

¹ To whom correspondence should be addressed: Cancer Research Facility, University of New Mexico, 915 Camino de Salud, CRF 117, Albuquerque, NM 87131. Tel.: 505-272-5583; Fax: 505-272-2841; E-mail: RDahl{at}salud.unm.edu.

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