title: Regulation of progranulin expression in myeloid cells.
abstract: Progranulin (pgrn; granulin-epithelin precursor, PC-cell-derived growth factor, or acrogranin) is a multifunctional secreted glycoprotein implicated in tumorigenesis, development, inflammation, and repair. It is highly expressed in macrophage and monocyte-derived dendritic cells. Here we investigate its regulation in myeloid cells. All-trans retinoic acid (ATRA) increased pgrn mRNA levels in myelomonocytic cells (CD34(+) progenitors; monoblastic U-937; monocytic THP-1; progranulocytic HL-60; macrophage RAW 264.7) but not in nonmyeloid cells tested. Interleukin-4 impaired basal expression of pgrn in U-937. Differentiation agents DMSO, and, in U-937 only, phorbol ester [phorbol 12-myristate,13-acetate (PMA)] elevated pgrn mRNA expression late in differentiation, suggestive of roles for pgrn in more mature terminally differentiated granulocyte/monocytes rather than during growth or differentiation. The response of pgrn mRNA to ATRA differs in U-937 and HL-60 lineages. In U-937, ATRA and chemical differentiation agents greatly increased pgrn mRNA stability, whereas, in HL-60, ATRA accelerated pgrn mRNA turnover. The initial upregulation of pgrn mRNA after stimulation with ATRA was independent of de novo protein synthesis in U-937 but not HL-60. Chemical blockade of nuclear factor-kappaB (NF-kappaB) activation impaired ATRA-stimulated pgrn expression in HL-60 but not U-937, whereas in U-937 it blocked PMA-induced pgrn mRNA expression, suggestive of cell-specific roles for NF-kappaB in determining pgrn mRNA levels. We propose that: 1) ATRA regulates pgrn mRNA levels in myelomonocytic cells; 2) ATRA acts in a cell-specific manner involving the differential control of mRNA stability and differential requirement for NF-kappaB signaling; and 3) elevated pgrn mRNA expression is characteristic of more mature cells and does not stimulate differentiation.
authors.affiliation: Endocrine Research Laboratories, Department of Medicine, Royal Victoria Hospital, McGill University, 687 Pine Avenue West, Montreal, Quebec, Canada.
authors.forename: Colin H P
authors.initials: CH
authors.lastname: Ong
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: He
authors.forename: Leonid
authors.initials: L
authors.lastname: Kriazhev
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.forename: Roger G E
authors.initials: RG
authors.lastname: Palfree
authors.forename: Andrew
authors.initials: A
authors.lastname: Bateman
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015847:Interleukin-4 / Q000008:administration & dosage*; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000077153:Progranulins; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D015847:Interleukin-4; D014212:Tretinoin