Expression, processing, and secretion of the neuroendocrine VGF peptides by INS-1 cells

The neurotropin-inducible gene vgf is expressed in neuronal and endocrine t issues. It encodes a secretory protein that is proteolytically processed in neuronal cells to low molecular mass polypeptides. In the present report, we show that vgf is expressed in different insulinoma cell lines and in nor mal rat pancreatic islets. In the insulinoma-derived beta-cell line INS-1, vgf messenger RNA was transcriptionally up-regulated by increased levels of intracellular cAMP, but not by the addition of glucose (20 mM) or phorbol 12-myristate 13-acetate (100 nM). Furthermore, nerve growth factor failed t o stimulate vgf gene expression. In INS-1 cells, the VGF protein was shown to be processed in a post endoplasmic reticulum compartment to produce a pe ptide profile similar to that seen in neurons. The release of such VGF pept ides occurred at a low rate in the absence of secretory stimuli (<2%/h). A 3-fold increase in the rate of release was seen after the addition of gluco se (15 mM), a 4-fold increase was seen after (Bu)(2)cAMP (1 mM), and a 6-fo ld increase was seen after phorbol la-myristate 13-acetate (100 nM). These results indicated that insulin-containing cells produce VGF-derived peptide s that are released via a regulated pathway in response to insulin secretag ogues.