Disease relevance of Grn

• Pgrn is highly expressed in aggressive cancer cell lines and clinical specimens including breast, ovarian, and renal cancers as well as gliomas [1].
• We found that acrogranin (also named PCDGF or progranulin) is overexpressed in uterine leiomyosarcoma [2].
• PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells [3].
• Progranulin (pgrn; PC-cell-derived growth factor, epithelin precursor, or acrogranin) has been identified recently as an autocrine regulator of tumorigenesis in several cancer cells including SW-13 adrenal carcinomas and some breast cancers, but how pgrn promotes tumor progression is not well understood [4].
• PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma [5].

High impact information on Grn

• When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound [6].
• Progranulin (PC-cell-derived growth factor/acrogranin) regulates invasion and cell survival [4].
• Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo [7].
• We propose that the rate of growth for some epithelia, such as SW-13 and MDCK, is proportional to the level of intrinsic progranulin gene expression, and that elevated progranulin gene expression confers a transformed phenotype on epithelial cells including anchorage independence in vitro and growth as tumors in nude mice [7].
• Progranulin is a 593-amino acid glycoprotein, the mRNA of which is expressed by many epithelial cells both in vitro and in vivo, but the biological significance of this expression is unclear [7].

Chemical compound and disease context of Grn

• PURPOSE: We have shown previously that the 88 kDa glycoprotein PC cell-derived growth factor (PCDGF/GP88) is expressed and acts as an autocrine growth factor in human multiple myeloma cells [5].
• Stimulation of PC cell-derived growth factor (epithelin/granulin precursor) expression by estradiol in human breast cancer cells [8].

Biological context of Grn

• Progranulin (Pgrn) is a pluripotent secreted growth factor that mediates cell cycle progression and cell motility [1].
• The existence of a large molecular mass precursor for granulin or epithelin has been predicted based upon recently cloned cDNAs encoding these biomolecules within a 63.5-kDa protein with putative glycosylation sites [9].
• Since one hallmark of embryo development is the formation of an epithelium, the trophectoderm, we tested the hypothesis that one such embryo-derived growth factor is acrogranin (epithelin/granulin precursor), a factor that possesses growth-regulatory activities principally toward epithelial cells [10].
• Based on the pattern of progranulin gene expression, we propose proliferative and developmental roles for progranulin in establishing pregnancy, during gastrulation, and during embryonic development of the epidermis, nervous system, blood vessel, formation, and spermatogenesis [11].
• Exon/intron organization of the gene encoding the mouse epithelin/granulin precursor (acrogranin) [12].

Anatomical context of Grn

• The malignancy of highly tumorigenic progranulin-expressing cell lines depends on the expression level of the pgrn gene since attenuating pgrn mRNA levels in pgrn-responsive cells greatly inhibits tumor progression [1].
• The present results indicate that PCDGF is a potential precursor for epithelin and/or granulin, that this 88-kDa protein is secreted and glycosylated, and that it can function as a mitogen for 3T3 cells as well as an autocrine growth factor for PC cells [9].
• Effects of progranulin on blastocyst hatching and subsequent adhesion and outgrowth in the mouse [13].
• Progranulin was localized exclusively to the surface of the trophectoderm in early and pre- and postadhesion blastocysts as well as in trophoblast cells and ICM of outgrowth embryos, being secreted as a single, 88-kDa form into the surrounding medium [13].
• We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury [6].

Associations of Grn with chemical compounds

• Digestion with peptide-N-glycosidase F yielded an apparent 68-kDa protein component indicating that PCDGF is a glycoprotein containing about 20 kDa of carbohydrate [9].
• Partial sequence from Edman degradation of peptide fragments obtained by digestion of PCDGF with cyanogen bromide and trypsin demonstrates that PCDGF contains regions of sequence identity to that deduced from the granulin or epithelin precursor cDNAs [9].
• Studies of bromodeoxyuridine incorporation and immunodissection of the ICM revealed that progranulin was effective on the trophectoderm but not on the ICM [13].
• We show that 17-beta-estradiol stimulates PCDGF mRNA and protein expression in a time and dose-dependent manner [8].
• 125I-PCDGF was chemically crosslinked to cell surface receptors on CCL64 cells with disuccinimidyl suberate [14].

Other interactions of Grn

• Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor) [10].
• The granulin/epithelin precursor abrogates the requirement for the insulin-like growth factor 1 receptor for growth in vitro [15].

Analytical, diagnostic and therapeutic context of Grn

• We used in situ hybridization to investigate progranulin expression in murine embryos [11].
• Using cDNA microarray methodology, we have shown previously that transcripts of progranulin gene (Grn, also known as acrogranin), a recently identified autocrine growth factor, were upregulated in mouse blastocysts adhered to the filter membrane in an in vitro-culture system [13].
• The growth factor, purified to homogeneity by SDS-polyacrylamide gel electrophoresis, was identified as the granulin/epithelin precursor by an accurate determination of the masses of endoproteinase Lys-C peptides using matrix-assisted laser desorption ionization mass spectrometry, followed by a data base search [15].
• CONCLUSION: These data suggest that expression of PCDGF/GP88 confers resistance to dexamethasone and increase tumorigenesis of multiple myeloma cells in mouse xenografts [5].
• Using Northern blot and western blot analyses, we detect the expression of PCDGF mRNA and protein in MCF-7 human breast cancer cells [8].

References