Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

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

21628454

DOI

10.1074/jbc.M110.197533

Abstract

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

Authors

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




Scopus

2-s2.0-80051694778   18 Citations

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

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