Regulated transcription of targeted genes and other biological events

US6063625A · kind A · utility

Assignees

• Board of Trustees of the Leland S. Stanford, Jr. University · US
• President and Fellows of Harvard College · US

Inventors

• Gerald R. Crabtree · Woodside, US
• Stuart L. Schreiber · Cambridge, US
• David Spencer · Houston, US
• Thomas J. Wandless · Cambridge, US
• Steffan N. Ho · San Diego, US
• Peter Belshaw · Madison, US

Key dates

• Filing date: Sep 16, 1998
• Grant date: May 16, 2000
• Expiry date: Sep 16, 2018

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07K2319/90
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities…