title: 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.
authors.affiliation: Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA 02115, USA. sandra.ryeom@childrens.harvard.edu
authors.forename: Sandra
authors.initials: S
authors.lastname: Ryeom
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rioth
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Lynch
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaslavsky
authors.forename: Amy
authors.initials: A
authors.lastname: Birsner
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D002455:Cell Division / Q000235:genetics; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D007700:Kinetics; D051379:Mice; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000235:genetics
chemical_list: D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D019703:Calcineurin