Calcineurin a-binding protein, a novel modulator of the calcineurin-nuclear factor of activated T-cell signaling pathway, is overexpressed in wilms' tumors and promotes cell migration.
Current therapeutic strategies against Wilms' tumor (WT) reach 80% to 85% success rate. In spite of this, a remaining 15% to 20% of tumors relapse and are associated with increased metastasis and poor prognosis. To identify new regulators of WT progression, we screened for developmental target genes of Pax2, a key regulator of kidney development and a WT signature gene. We show that one of these target genes, calcineurin A-binding protein (CnABP), is coexpressed with Pax2 during kidney development and is overexpressed in >70% of WT samples analyzed. The CnABP gene encodes a novel protein product conserved in higher vertebrates. We show that CnABP promotes cell proliferation and migration in cell culture experiments. Biochemical analyses additionally identified an interaction between CnABP and calcineurin Abeta, the catalytic subunit of the calcium-responsive serine/threonine phosphatase calcineurin. We show that this interaction leads to the inhibition of calcineurin phosphatase activity and prevents nuclear factor of activated T-cell (NFAT) nuclear translocation. Inhibition of NFAT nuclear localization results in decreased NFAT transcriptional response. Together, these data identify a new modulator of calcineurin signaling up-regulated in WTs.
Nguyen
Alana H T
AH
Goodman Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Béland
Mélanie
M
Gaitan
Yaned
Y
Bouchard
Maxime
M
D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism*; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D014158:Transcription, Genetic; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D050778:NFATC Transcription Factors; D051762:PAX2 Transcription Factor; D010750:Phosphoproteins; D019703:Calcineurin