Serpinin: A novel chromogranin a-derived, secreted peptide up-regulates protease nexin-1 expression and granule biogenesis in endocrine cells

Hisatsugu Koshimizu, Niamh X. Cawley, Taeyoon Kim, Alfred L. Yergey, Y. Peng Loh

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Previously we demonstrated that chromogranin A (CgA) promoted secretory granule biogenesis in endocrine cells by stabilizing and preventing granule protein degradation in the Golgi, through up-regulation of expression of the protease inhibitor, protease nexin-1 (PN-1). However, the mechanism by which CgA signals the increase of PN-1 expression is unknown. Here we identified a 2.9-kDa CgA-C-terminus peptide, which we named serpinin, in conditioned media from AtT-20 cells, a corticotroph cell line, which up-regulated PN-1 mRNA expression. Serpinin was secreted from AtT-20 cells upon high potassium stimulation and increased PN-1 mRNA transcription in these cells, in an actinomycin D-inhibitable manner. CgA itself and other CgA-derived peptides, when added to AtT-20 cell media, had no effect on PN-1 expression. Treatment of AtT-20 cells with 10 nM serpinin elevated cAMP levels and PN-1 mRNA expression, and this effect was inhibited by a protein kinase A inhibitor, 6-22 amide. Serpinin and a cAMP analog, 8-bromo-cAMP, promoted the translocation of the transcription factor Sp1 into the nucleus, which is known to drive PN-1 expression. Additionally, an Sp1 inhibitor, mithramycin A inhibited the serpinin-induced PN-1 mRNA up-regulation. Furthermore, a luciferase reporter assay demonstrated serpinin-induced up-regulation of PN-1 promoter activity in an Sp1- dependent manner. When added to CgB-transfected 6T3 cells, a mutant AtT20 cell line, serpinin induced granule biogenesis as evidenced by the presence of CgB puncta accumulation in the processes and tips. Our findings taken together show that serpinin, a novel CgA-derived peptide, is secreted upon stimulation of corticotrophs and plays an important autocrine role in up-regulating PN-1-dependent granule biogenesis via a cAMP-protein kinase A-Sp1 pathway to replenish released granules.

Original languageEnglish
Pages (from-to)732-744
Number of pages13
JournalMolecular Endocrinology
Volume25
Issue number5
DOIs
Publication statusPublished - 05-2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'Serpinin: A novel chromogranin a-derived, secreted peptide up-regulates protease nexin-1 expression and granule biogenesis in endocrine cells'. Together they form a unique fingerprint.

  • Cite this