RESUMO
Subunit 6 of the COP9 signalosome complex, CSN6, is known to be critical to the regulation of the MDM2-p53 axis for cell proliferation and anti-apoptosis, but its many targets remain unclear. Here we show that p57 (Kip2) is a target of CSN6, and that CSN6 is a negative regulator of p57 (Kip2) . CSN6 associates with p57 (Kip2) , and its overexpression can decrease the steady-state expression of p57 (Kip2) ; accordingly, CSN6 deficiency leads to p57 (Kip2) stabilization. Mechanistic studies show that CSN6 associates with p57 (Kip2) and Skp2, a component of the E3 ligase, which, in turn, facilitates Skp2-mediated protein ubiquitination of p57 (Kip2) . Loss of Skp2 compromised CSN6-mediated p57 (Kip2) destabilization, suggesting collaboration between Skp2 and CSN6 in degradation of p57 (Kip2) . CSN6's negative impact on p57 (Kip2) elevation translates into cell growth promotion, cell cycle deregulation and potentiated transformational activity. Significantly, univariate Kaplan-Meier analysis of tumor samples demonstrates that high CSN6 expression or low p57 expression is associated with poor overall survival. These data suggest that CSN6 is an important negative regulator of p57 (Kip2) , and that overexpression of CSN6 in many types of cancer could lead to decreased expression of p57 (Kip2) and result in promoted cancer cell growth.
Assuntos
Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Complexos Multiproteicos/metabolismo , Peptídeo Hidrolases/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Complexo do Signalossomo COP9 , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p57/genética , Humanos , Estimativa de Kaplan-Meier , Camundongos , Complexos Multiproteicos/genética , Células NIH 3T3 , Peptídeo Hidrolases/genética , Ligação Proteica/genética , Ligação Proteica/fisiologiaRESUMO
The transcription factor nuclear factor kappaB (NF-kappaB) is widely expressed in the nervous system and increased NF-kappaB immunoreactivity has been observed in Alzheimer's disease (AD) brains in the nuclei of neurons within the vicinity of diffuse beta-amyloid plaques. Beta-amyloid (Abeta) peptides are the main constituent of senile plaques and are known to stimulate NF-kappaB activity. In the present study, we investigated the effect of various NF-kappaB inhibitors on the production of Abeta1-40, Abeta1-42, secreted APP (sAPPbeta and sAPPalpha) and APP C-terminal fragments (APP-CTF) using CHO cells overexpressing the beta-amyloid precursor protein (APP). Our data show that NF-kappaB inhibitors decrease both Abeta1-40 and Abeta1-42 production. In addition, we show that some NF-kappaB inhibitors decrease sAPPbeta and APP-CTFbeta suggesting that they reduce the beta-secretase cleavage of APP. Altogether our data suggest that NF-kappaB inhibitors may be of therapeutic importance for the treatment of AD pathology not only by blocking inflammatory processes but also by directly inhibiting the production of Abeta peptides.
