Accession Number:

ADA422557

Title:

Are Microtubules Involved in Anoikis?

Descriptive Note:

Final rept. 1 Aug 2000-31 Jul 2003

Corporate Author:

BURNHAM INST LA JOLLA CA

Personal Author(s):

Report Date:

2003-08-01

Pagination or Media Count:

23.0

Abstract:

This project is investigating the role of microtubule alterations in anoikis, with a view toward re-examining the mechanism of microtubule-targeting drugs such as taxol. During the past year, we have uncovered a new mechanism by which cell adhesion controls apoptosis. The death receptor adaptor protein FADD FAS-associated death domain protein is critical for anoikis as well as death ligand e.g., FASL induced apoptosis. Recently, we discovered that FADD is primarily in the nucleus of attached cells, where it is unavailable for apoptosis induction. Detachment of mammary epithelial cells form extracellular matrix, however, provokes the export of FADD form the nucleus, thus promoting apoptosis. Our preliminary work suggests that microtubule drugs can promote FADD export, suggesting a new mechanism by which the can promote apoptosis. This is expected to have major ramifications for optimizing the use of taxol or other microtubule drugs in connection with other agents that may promote apoptosis. During the latter year of the project, we found that a protein kinase known as Glycogen Synthase Kinase-3 GSK-3 phosphorylates FADD and that this phosphorylation is required for both the transport of FADD into and out of the nucleus. In that GSD-3 is a microtubule-regulatory kinase, this represents a new link between microtubules and apoptosis.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE