ArticleThe Journal of biological chemistry2011
Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 30 citations in OpenAlex.
- GSK3βGut · 2026Article
- Kujiol A Inhibits Interferon-γ and Interleukin-2 Expression and the NFATc2 Interaction with Their Promoters in T Cells.Molecules (Basel, Switzerland) · 2026Article
- Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3.Cell death and differentiation · 2022Article
- Glycogen synthase kinase-3β: a novel therapeutic target for pancreatic cancer.Expert opinion on therapeutic targets · 2020Review
- An actionable axis linking NFATc2 to EZH2 controls the EMT-like program of melanoma cells.Oncogene · 2019Article
- PAX7 expression in sarcomas bearing the EWSR1-NFATC2 translocation.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2019Article
- Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases.Frontiers in immunology · 2018Review
- MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies.Oncogene · 2016Review
- GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression.Molecular cancer therapeutics · 2016Article
- Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA.Oncotarget · 2015Article
- NFATc1 as a therapeutic target in FLT3-ITD-positive AML.Leukemia · 2015Article
- NFAT as cancer target: mission possible?Biochimica et biophysica acta · 2014Review
- c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.Cell death & disease · 2014Article
- Zoledronic acid inhibits human nasopharyngeal carcinoma cell proliferation by activating mitochondrial apoptotic pathway.Medical oncology (Northwood, London, England) · 2012Article
- The 'N-factors' in pancreatic cancer: functional relevance of NF-κB, NFAT and Nrf2 in pancreatic cancer.Oncogenesis · 2012Article
- Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer.Gastroenterology · 2012Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.