Targeted Deletion of the Calcineurin Inhibitor DSCR1 Suppresses Tumor Growth

Abstract

The NF-AT transcription factors regulated by the phosphatase calcineurin play a role in breast cancer metastasis-promoting tumor cell invasion. Metastasis is a multistep process requiring angiogenesis and endothelial activation. NF-AT is also expressed in endothelial cells, and calcineurin-NF-AT signaling is an important downstream effector of the proangiogenic cytokine VEGF. One isoform of the endogenous calcineurin regulator, Down syndrome candidate region-1 (DSCR1.Ex4), suppresses calcineurin-NFAT signaling blocking endothelial proliferation. However, overexpression of the other DSCR1 isoform (DSCR1.Ex1) may promote angiogenesis. We report that targeted deletion of both isoforms leads to hyperactivated calcineurin and precocious endothelial apoptosis, inhibiting formation of an effective tumor vasculature and suppressing tumorigenesis. Treatment with the specific pharmacological calcineurin inhibitor cyclosporin A rescues this endothelial defect in DSCR1(-/-) mice, restoring tumor growth.

Cyclin D1 Is a Bona Fide Target Gene of NFATc1 and Is Sufficient in the Mediation of Injury-induced Vascular Wall Remodeling

“…In infantile hemangiomas, suppression of NFAT-dependent VEGFR1 expression was reported to be associated with altered VEGFR2 signaling (14). In addition, depletion of calcineurin inhibitor, DSCR1, has been shown to prevent tumor growth (13). Based on these findings, it appears that NFAT isoforms carry out differential roles in the regulation of cell proliferation and/or differentiation in different cell types.…”

“…In addition, a large body of evidence indicates a role for calcineurin-NFAT signaling in the regulation of pathological cardiac hypertrophy (11,12). In contrast, suppression of an endogenous calcineurin inhibitor, DSCR1 (Down syndrome candidate region-1), in endothelial cells leads to hyperactivation of calcineurin, which results in precocious endothelial cell apoptosis, thereby inhibiting tumorigenesis (13). Furthermore, in infantile hemangiomas (the tumors of endothelial cell origin), increased VEGFR2 signaling was found to be linked to suppression of NFAT-dependent expression of VEGFR1 (14).…”

Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells

“…Furthermore, we linked increased dosage of DYRK1A and DSCR1 to reduced nuclear levels of transcription factor NFATc. It is known that nuclear export of the NFATc family of transcription factors is accelerated upon its phosphorylation by DYRK1A (Arron et al 2006;Gwack et al 2006) and that their nuclear import is suppressed by DSCR1 through deactivation of calcineurin (Ryeom et al 2008), an important regulator for nuclear entry of NFATc. Consistently, we found that overexpression of DYRK1A and DSCR1 diminished nuclear occupancy of NFATc in progenitors.…”

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

“…Ppp3cc, also known as calcineurin A subunit, is a Ca2 þ -and calmodulin-dependent serine/threonine protein phosphatase. In a recent study, calcineurin was shown to promote tumour cell invasion via transcriptional factor NFAT in breast cancer metastasis 40 . Lats2 is a serine/threonine protein kinase belonging to the tumour suppressor family, and has been reported to participate in p53 signalling 41 and to be implicated in cell cycle regulation, apoptosis, centrosome duplication and genomic stability [42][43][44] .…”