Research Article

Regulation of Protein Secretion Through Controlled Aggregation in the Endoplasmic Reticulum

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Science  04 Feb 2000:
Vol. 287, Issue 5454, pp. 826-830
DOI: 10.1126/science.287.5454.826

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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.

  • * To whom correspondence should be addressed. E-mail: vrivera{at}ariad.com and clackson{at}ariad.com

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