Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum Journal Article
| Authors: | Rivera, V. M.; Wang, X.; Wardwell, S.; Courage, N. L.; Volchuk, A.; Keenan, T.; Holt, D. A.; Gilman, M.; Orci, L.; Cerasoli, F. Jr; Rothman, J. E.; Clackson, T. |
| Article Title: | Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum |
| Abstract: | A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small- molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery. |
| Keywords: | nonhuman; animal cell; animals; mice; cell line; tumor cells, cultured; animalia; drug delivery systems; endoplasmic reticulum; kinetics; recombinant fusion proteins; protein transport; gene therapy; human growth hormone; protein secretion; ligands; insulin; glucose blood level; blood glucose; furin; protein aggregation; diabetes mellitus, experimental; golgi apparatus; protein engineering; tacrolimus binding proteins; proinsulin; humans; priority journal; article; immunophilins; subtilisins |
| Journal Title: | Science |
| Volume: | 287 |
| Issue: | 5454 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2000-02-04 |
| Start Page: | 826 |
| End Page: | 830 |
| Language: | English |
| DOI: | 10.1126/science.287.5454.826 |
| PUBMED: | 10657290 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work