CHIP stabilizes XXXX via proteasomal degradation and @entity876 -mediated trans-repression of b-secretase.

@entity1 @entity6705 @entity527 @entity477 @entity876 @entity195
UNASSIGNED: In @entity1 with @entity195 ( @entity195 ), deposition of amyloid-beta Ab, a proteolytic cleavage of @entity477 ( @entity477 ) by b-secretase/ @entity6705 , forms @entity527 in the brain. @entity6705 activation is caused due to oxidative stresses and dysfunction of ubiquitin-proteasome system (UPS), which is linked to @entity876 inactivation. As partial suppression of @entity6705 attenuates Ab generation and @entity195 -related pathology, it might be an ideal target for @entity195 treatment. We have shown that both in neurons and in HEK- @entity477 cells, @entity6705 is a new substrate of E3-ligase CHIP and an inverse relation exists between CHIP and @entity6705 level. CHIP inhibits ectopic @entity6705 level by promoting its ubiquitination and proteasomal degradation, thus reducing @entity477 processing; it stabilizes @entity477 in neurons, thus reducing Ab. CHIP(U) (box) domain physically interacts with @entity6705 ; however, both U-box and TPR domain are essential for ubiquitination and degradation of @entity6705 . Further, @entity6705 is a downstream target of @entity876 and overexpression of @entity876 decreases @entity6705 level. In HEK- @entity477 cells, CHIP is shown to negatively regulate @entity6705 promoter through stabilization of @entity876 's DNA-binding conformation and its binding upon 5' UTR element (+127 to +150). We have thus discovered that CHIP regulates @entity876 -mediated trans-repression of @entity6705 at both transcriptional and post-translational level. We propose that a CHIP- @entity6705 - @entity876 feedback loop might control @entity477 stabilization, which could further be utilized for new therapeutic intervention in @entity195 .
