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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3911-3917.
Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2003-10-3688.


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Submitted October 29, 2003
Accepted July 28, 2004

Expression of C/EBP Homologous Protein (CHOP) is Regulated by Retinoic Acid, and CHOP Negatively Regulates Myeloid Target Genes

Sigal Gery*, Dorothy J Park, Peter T Vuong, Doris Y Chih, Nathan Lemp, and H P Koeffler

Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

* Corresponding author; email: gerys{at}cshs.org.

Retinoic acid (RA) promotes granulocytic differentiation of normal hematopoietic cells as well as acute promyelocytic leukemia (APL) blasts by transcriptional modulation of myeloid regulatory genes. In this study, we have identified the C/EBP Homologous Protein (CHOP) as a novel retinoid responsive gene using a PCR-based cDNA subtraction method. All-trans retinoic acid (ATRA) induced a biphasic expression of CHOP mRNA in the NB4 and HL60 AML cell lines. Level of CHOP expression increased within 1 hour of exposure to ATRA, its expression became nearly absent between 6 to 24 hours, and a second phase of induction occurred after 48 hours. Retinoid-dependent regulation of CHOP expression was also observed in normal human neutrophils, but not in peripheral blood mononuclear cells. In addition, retinoid-dependent regulation of CHOP expression was not observed in the retinoid non-responsive cell lines HL60R and NB4-R2. CHOP expression was regulated at the transcriptional level and was independent of new protein synthesis. CHOP heterodimerized with C/EBP{epsilon} and negatively regulated the myeloid specific gene, lactoferrin. Furthermore, CHOP transcriptionally inhibited C/EBP{alpha} and -{epsilon}-dependent induction of secondary granule gene expression. Taken together, RA signaling in granulocytic differentiation involves regulated expression of CHOP and C/EBP{epsilon} in a coordinated fashion.


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