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.

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@article{Rivera2000RegulationOP, title={Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum.}, author={V M Rivera and X Wang and S Wardwell and N L Courage and A Volchuk and T Keenan and D A Holt and M Gilman and L Orci and F Cerasoli and J E Rothman and T Clackson}, journal={Science}, year={2000}, volume={287 5454}, pages={826-30} }