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Differential activation of the calcium/protein kinase C and the canonical β‐catenin pathway by Wnt1 and Wnt7a produces opposite effects on cell proliferation in PC12 cells
Author(s) -
Spinsanti Paola,
De Vita Teresa,
Caruso Alessandra,
Melchiorri Daniela,
Misasi Roberta,
Caricasole Andrea,
Nicoletti Ferdinando
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05111.x
Subject(s) - wnt signaling pathway , microbiology and biotechnology , biology , nfat , transcription factor , cell growth , signal transduction , chemistry , biochemistry , gene
J. Neurochem . (2008) 104, 1588–1598. Abstract We examined the effect of Wnt1 and Wnt7a on cell proliferation using undifferentiated PC12 cells, which originate from the neural crest and are widely employed as a neuronal cell model. Heterologous expression of Wnt1 enhanced [ 3 H]thymidine incorporation and expression of cyclin D1 and cylin E in PC12 cells. Opposite effects were observed in PC12 cells expressing Wnt7a. Searching for the mechanisms underlying the opposite effects of Wnt1 and Wnt7a on PC12 cell proliferation, we examined the activation of the canonical β‐catenin/T‐cell–lymphoid enhancer‐binding protein transcription factor pathway and the ‘calcium pathway’ by co‐transfecting the cells with a reporter gene controlled by either T‐cell–lymphoid enhancer‐binding protein transcription factor or the calcium‐activated transcription factor, NFAT. Wnt1 and Wnt7a activated both pathways, but to a different extent. While Wnt1 preferentially activated the calcium pathway, Wnt7a mainly activated the canonical pathway. Pharmacological inhibition of protein kinase C, which is a component of the calcium pathway, abrogated the increase in cell proliferation induced by Wnt1 without affecting the antiproliferative action of Wnt7a. The action of Wnt7a was instead occluded by lithium ions, which mimic the activation of the canonical pathway, and was largely reduced by Dickkopf‐1, which acts as an inhibitor of the canonical pathway. In addition, expression of a constitutively active mutant of β‐catenin potently activated the canonical Wnt pathway and reduced [ 3 H]thymidine incorporation. These data challenge the view that the canonical Wnt pathway invariably supports cell growth and suggest that, at least in PC12 cells, cell proliferation is regulated by the balance between the calcium/protein kinase C pathway and the canonical pathway.