The human progranulin gene encodes a 593 amino acid secreted glycoprotein, progranulin (also called PC cell-derived growth factor, acrogranin or granulin/epithelin precursor). The biological activities of this protein were poorly defined at the beginning of the project. Here, we determined that the progranulin gene is widely expressed in vivo and strongly associated with immune, neuronal and highly proliferative epithelial cells. It is not expressed in fibroblasts and endothelial cells in vivo unless these cells are stimulated by, for example, tissue damage and this expression correlates temporally with the healing process. Thus progranuhn is induclbly expressed in mesenchymal cells but is a constitutive product in proliferative epithelial cells. These studies defined a physiological context for investigating the roles of progranulin in the body. To correlate the expression studies with function, we assessed the ability of progranulin to regulate wound repair and epithelial growth. Progranulin enhances the growth and motility of fibroblasts and endothelial cells, and promotes the formation of tubule-like structures by endothelial cells on Matrigel, suggesting that progranulin may accelerate fibroplasia and serve as a pro-angiogenic factor in the proper environment. These effects are mediated through the activation of the p44/42 MAP kinase, PI-3 kinase and focal adhesion kinase (FAK) pathways, as inlubition of the MAP kinase and PI-3 kinase pathways by PD98059 and wortmannin blocked progranulin-induced cell migration, and progranulin was found to hyper-phosphorylate FAK in endothelial cells. The association of strong progranulin expression with highly proliferative epithelial cells suggests that progranulin may take part in epithelial homeostasis. To investigate this hypothesis, we either overexpressed or downregulated the progranulin gene in SW-13 and MDCK cells. SW-13 cells are derived from human adrenal cancer, but their growth resembles non-transformed epithel
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37898 |
| Date | January 2001 |
| Creators | He, Zhiheng, 1971- |
| Contributors | Bateman, Andrew (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001837479, proquestno: NQ75640, Theses scanned by UMI/ProQuest. |
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