Article Figures & Data
Figures
- Fig. 1.
The molecular target of 17-AAG is the chaperone HSP90, which, depending on its conformation, recruits various cochaperones to assemble two distinct multichaperone complexes. One complex (I) favors the proteasome-dependent degradation of HSP90 client proteins, whereas the other complex stabilizes HSP90 client proteins. 17-AAG binding to HSP90 removes the conformational flexibility of the chaperone, resulting in accumulation of the proteasome-targeting HSP90-based multichaperone complex with concomitant loss of the client protein stabilizing HSP90 complex. The result is coordinated degradation of the HSP90 clients HER-2, Akt, Raf-1, and androgen receptor.
- Fig. 2.
17-AAG inhibits the androgen receptor itself, as well as multiple components of HER-2-stimulated upstream signaling pathways that converge to enhance the transcriptional activity of the receptor. In hormone-refractory prostate cancer, at least two HER-2 driven signaling cascades, the Akt kinase pathway and the MAP kinase pathway, converge on the androgen receptor, phosphorylate it at multiple sites, and stimulate its transcriptional activity. 17-AAG promotes the destabilization and degradation of HER-2, Akt kinase, Raf-1 kinase, and wild-type and mutated forms of the androgen receptor. Additionally, 17-AAG inhibits the transcriptional activity of the androgen receptor.
Volume 8, Issue 5
