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Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid. J Biol Chem 2011 Aug 19;286(33):28761-71 PMID: 21628454 PMCID: PMC3190684

Pubmed ID





The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

Author List

Singh SK, Baumgart S, Singh G, König AO, Reutlinger K, Hofbauer LC, Barth P, Gress TM, Lomberk G, Urrutia R, Fernandez-Zapico ME, Ellenrieder V


Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin


2-s2.0-80051694778   18 Citations

MESH terms used to index this publication - Major topics in bold

Active Transport, Cell Nucleus
Antineoplastic Agents
Bone Density Conservation Agents
Breast Neoplasms
Cell Nucleus
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Mice, Nude
NFATC Transcription Factors
Neoplasm Proteins
Pancreatic Neoplasms
Protein Stability
Protein Structure, Tertiary
Proto-Oncogene Proteins c-mdm2
Signal Transduction
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad