Zoledronic Acid Inhibits Cancer Growth: Molecular Characterization of Zoledronic acid Induced Growth Inhibition in Cancer - Couverture souple

Singh, Dr.Shiv Kishor; Garima Singh, Dr.; Dr. Volker Ellenrieder, Prof.

 
9783639365443: Zoledronic Acid Inhibits Cancer Growth: Molecular Characterization of Zoledronic acid Induced Growth Inhibition in Cancer
Couverture souple
ISBN 10 : 3639365445 ISBN 13 : 9783639365443
Editeur : VDM Verlag Dr. Müller, 2011

Synopsis

The aminobisphosphonate zoledronic acid(ZOL) has elicited significant attention due to its remarkable anti-tumoral activity,though its detailed mechanism of action remains unclear. Here,we demonstrate the existence of a nuclear GSK3-NFATc2 stabilization pathway that promotes cancer growth in vitro and in vivo and serves as a bonafide target of ZOL. Specifically, the serine/threonine kinase GSK3 stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2 mediated proteolysis. ZOL disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK3 inhibition and induction of HDM2 activity. Upon nuclear accumulation,HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues K-684/K-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis induced constitutive serine phosphorylation of the SP2 domain prevents NFATc2 from HDM2 mediated ubiquitination and degradation by ZOL. In conclusion, this report demonstrates a critical role of the GSK3-HDM2 signaling loop in the regulation of NFATc2 protein stability.

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Présentation de l'éditeur

The aminobisphosphonate zoledronic acid(ZOL) has elicited significant attention due to its remarkable anti-tumoral activity,though its detailed mechanism of action remains unclear. Here,we demonstrate the existence of a nuclear GSK3-NFATc2 stabilization pathway that promotes cancer growth in vitro and in vivo and serves as a bonafide target of ZOL. Specifically, the serine/threonine kinase GSK3 stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2 mediated proteolysis. ZOL disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK3 inhibition and induction of HDM2 activity. Upon nuclear accumulation,HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues K-684/K-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis induced constitutive serine phosphorylation of the SP2 domain prevents NFATc2 from HDM2 mediated ubiquitination and degradation by ZOL. In conclusion, this report demonstrates a critical role of the GSK3-HDM2 signaling loop in the regulation of NFATc2 protein stability.

Biographie de l'auteur

Fight Against Cancer: Once You Choose Hope, Anything's Possible.

Les informations fournies dans la section « A propos du livre » peuvent faire référence à une autre édition de ce titre.

Éditeur
VDM Verlag Dr. Müller
Date d'édition
2011
Langue
anglais
ISBN 10 
3639365445
ISBN 13 
9783639365443
Reliure
Broché
Nombre de pages
120
Coordonnées du fabricant
non disponible
Personne responsable
non disponible