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 ϩ 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-B (NF-B) activation impaired ATRAstimulated pgrn expression in HL-60 but not U-937, whereas in U-937 it blocked PMA-induced pgrn mRNA expression, suggestive of cellspecific roles for NF-B 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-B signaling; and 3) elevated pgrn mRNA expression is characteristic of more mature cells and does not stimulate differentiation.granulin; stem cell factor; colony-stimulating factor THE GRANULIN-EPITHELIN precursor progranulin (pgrn; see Ref. 4), which is also called proepithelin (47), PC-cell-derived growth factor (66), or acrogranin (1), is a multifunctional regulatory protein that promotes mitosis, survival, and migration in many cell types (43). It stimulates growth factor-related signaling pathways such as the phosphorylation of shc, p44/42 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase B/AKT, and the p70 S6 kinase (24,35,65) and contributes to carcinogenesis in breast (51), ovarian (16,26), renal (18), hepatocellular (10), and prostate (44) cancers, gliomas (33), and multiple myelomas (63). Physiologically, pgrn is involved in wound repair (25,67) and is expressed during development (8) where it regulates cavitation in preimplantation embryos (17), blastocyst hatching (48), and malespecific differentiation of the neonatal hypothalamus (56,58).The granulin (GRN) gene is highly expressed in monocytederived cells, being the 17th and 30th most abundant transcript in human macrophage (9) and monocyte-derived dendritic cells (21), respectively. Peptides derived from pgrn, the granulin/ epit...

HDL/Apolipoprotein A-I Binds to Macrophage-Derived Progranulin and Suppresses its Conversion into Proinflammatory Granulins

“…It is reported to be involved in cancer progression 8) , development 12) , wound healing 13) , and myeloid cell proliferation 14) , whereas mutation of progranulin causes frontotemporal dementia 15,16) . In the present study, we demonstrated that the macrophage-secreted factor was approximately 130 kDa, while the purified protein identified as progranulin was 80 kDa.…”

“…The 130-kDa HDL binding protein might be a homodimer or heteromer that includes progranulin, which is known to be glycosylated and to have disulfide bonds 11) . Ong and colleagues 14) used myeloid cell lines and reported the overexpression of progranulin in macrophages and monocyte-derived dendritic cells, and that the level of expression was dependent on cell differentiation. Our results also demonstrated that the differentiation of human monocyte-derived macrophages was associated with increased expression levels of progranulin and that progranulin expression was regulated in an autocrine fashion in human monocytederived macrophages.…”

Proteomics analysis of regenerating amphibian limbs: changes during the onset of regeneration

“…Reference annexin 1 (Parente and Solito, 2004) annexin 2, annexin II type 1 (Abbas et al, 2005) annexin 5 (Munoz et al, 2007) B fibrinopeptide (Mosesson et al, 2001) calpactin I (annexin II) light chain p11 subunit (Laumonnier et al, 2006) complement component 1 q subcomponent binding protein (Abbas et al, 2005) elastase 2 (Horwitz et al, 2007) fibrinogen alpha (Ugarova and Yakubenko, 2001) fibrinogen gamma (Ugarova and Yakubenko, 2001) gelatinase B, matrixmetalloproteinase 9 (Abbas et al, 2005) granulin (Ong et al, 2006) integrin alpha V subunit (Schoeler et al, 2003) interferon regulatory factor 2 binding protein 2 (Childs and Goodbourn, 2003) lymphocyte cytosolic protein 1 (Abbas et al, 2005) manganese superoxide dismutase (Abbas et al, 2005) moesin (Abbas et al, 2005) myeloperoxidase, peroxidase 2 (Rutgers et al, 2003) phosphatidylserine decarboxylase (Abbas et al, 2005) prohibitin (Theiss et al, 2007) putative cathepsin L (Abbas et al, 2005) slingshot-related protein (Abbas et al, 2005) transaldolase 1 (Abbas et al, 2005) transferrin, lactotransferrin (Weinberg, 2007) vimentin (VIM1, VIM4) (Benes et al, 2006) Protein Name SC Types References actin beta MSC, NSC (Baharvand et al, 2007) actin gamma MSC, NSC (Baharvand et al, 2007) aldolase A ESC, MSC (Baharvand et al, 2007) annexin 1 MSC, NSC (Baharvand et al, 2007) annexin 2, annexin II type 1 MSC, NSC (Baharvand et al, 2007) annexin 5 MSC, NSC (Baharvand et al, 2007) annexin 7 MSC (Kim et al, 2006) ATP-dependent chromatin remodeling DEXH-box protein NSC (Matsumoto et al, 2006) ferritin ADSC (Zvonic et al, 2007) glutathione-S-transferase ADSC …”

Secreted Progranulin Is a Homodimer and Is Not a Component of High Density Lipoproteins (HDL)

“…At a cellular level, progranulin is a secreted growth factor expressed in epithelial cells, hematopoetic cells, adipocytes, immune cells, and certain types of neurons (3)(4)(5)(6)(7). Mutations in the GRN gene encoding progranulin are a leading cause of frontotemporal dementia (8,9).…”