Proepithelin, PEPI, PC Cell-derived Growth Factor

The granulins are a family of cysteine-rich polypeptides, some of which have growth modulatory activity. The widespread occurrence of granulin mRNA in cells from the hematopoietic system and in epithelia implies important functions in these tissues. All 4 known human granulin-like peptides are encoded in a single precursor, progranulin, which has a highly conserved 12-cysteine backbone defining a consensus sequence that is repeated 7 times. Progranulin is a 593-amino acid glycoprotein, the mRNA of which is expressed in many epithelial cells both in vitro and in vivo. He and Bateman demonstrated that overexpression of the progranulin gene in SW-13 adrenal carcinoma cells and MDCK nontransformed renal epithelia resulted in transfection-specific secretion of progranulin, acquired clonogenicity in semisolid agar, and increased mitosis in monolayer culture, whereas diminution of progranulin gene expression impaired growth of these cells. They proposed that the rate of growth of some epithelia 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. They also found 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. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels, and fibroblasts in the wound. It acted directly on isolated dermal fibroblasts and endothelial cells to promote division, migration, and the formation of capillary-like tubule structures, concluding that progranulin is, therefore, probably a wound-related growth factor. Due to its tumor-promoting activity and multiple functions on hematopoietic cells and endothelial cells, progranulin can be a novel marker for oncology and hematology.