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J. Biol. Chem., Vol. 278, Issue 27, 25133-25142, July 4, 2003

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Myeloid Expression of Cytochrome P450 4F3 Is Determined by a Lineage-specific Alternative Promoter^*

Peter Christmas  , Nadia Carlesso ¶, Haibo Shang , Shing-Ming Cheng , Brittany M. Weber , Frederic I. Preffer ||, David T. Scadden ¶ and Roy J. Soberman 

From the Renal Unit, ^¶AIDS Research Center and Cancer Center, and ^||Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

The cytochrome P450 4F3 (CYP4F3) gene encodes two functionally distinct enzymes that differ only by the selection of exon 4 (CYP4F3A) or exon 3 (CYP4F3B). CYP4F3A inactivates leukotriene B₄, a reaction that has significance for controlling inflammation. CYP4F3B converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a potent activator of protein kinase C. We have previously shown that mRNAs coding for CYP4F3A and CYP4F3B are generated from distinct transcription start sites in neutrophils and liver. We therefore investigated mechanisms that regulate the cell-specific expression of these two isoforms. Initially, we analyzed the distribution of CYP4F3 in human leukocytes and determined a lineage-specific pattern of isoform expression. CYP4F3A is expressed in myeloid cells and is coordinate with myeloid differentiation markers such as CD11b and myeloperoxidase during development in the bone marrow. In contrast, CYP4F3B expression is restricted to a small population of CD3+ T lymphocytes. We identified distinct transcriptional features in myeloid, lymphoid, and hepatic cells that indicate the presence of multiple promoters in the CYP4F3 gene. The hepatic promoter depends on a cluster of hepatocyte nuclear factor sites 123–155 bp upstream of the initiator ATG codon. The myeloid promoter spans 400 bp in a region 468–872 bp upstream of the ATG codon; it is associated with clusters of CACCT sites and can be activated by ZEB-2, a factor primarily characterized as a transcriptional repressor in cells that include lymphocytes. ZEB-2 interacts with C-terminal binding protein and Smads, and this would provide opportunities for integrating environmental signals in myelopoiesis and inflammation.

Received for publication, February 27, 2003 , and in revised form, April 15, 2003.

^* This work was supported by National Institutes of Health Grants DK59991 (to P. C.), HL68256 (to N. C.), DK52234 and HL55718 (to D. T. S.), and GM-61823 (to R. J. S.), a grant from the Richard Saltonstall Charitable Foundation (to D. T. S), and a grant from the Jewish Communal Fund (to R. J. S). 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.

To whom correspondence should be addressed: Renal Unit, Massachusetts General Hospital East, 149 The Navy Yard, 13th St., Charlestown, MA 02129. Tel.: 617-724-4336; Fax: 617-726-5669; E-mail: christma{at}helix.mgh.harvard.edu.

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				P. Christmas, K. Tolentino, V. Primo, K. Z. Berry, R. C. Murphy, M. Chen, D. M. Lee, and R. J. Soberman Cytochrome P-450 4F18 Is the Leukotriene B4 {omega}-1/{omega}-2 Hydroxylase in Mouse Polymorphonuclear Leukocytes: IDENTIFICATION AS THE FUNCTIONAL ORTHOLOGUE OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE CYP4F3A IN THE DOWN-REGULATION OF RESPONSES TO LTB4 J. Biol. Chem., March 17, 2006; 281(11): 7189 - 7196. [Abstract] [Full Text] [PDF]