Journal Article

Protein kinase C ζ is a positive modulator of canonical Wnt signaling pathway in tumoral colon cell lines

Luis Bernardo Luna-Ulloa, José G. Hernández-Maqueda, Paula Santoyo-Ramos, M.Cristina Castañeda-Patlán and Martha Robles-Flores

in Carcinogenesis

Volume 32, issue 11, pages 1615-1624
Published in print November 2011 | ISSN: 0143-3334
Published online August 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr190
Protein kinase C ζ is a positive modulator of canonical Wnt signaling pathway in tumoral colon cell lines

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The colonic epithelium is a continuously renewing tissue with a dynamic turnover of cells. Wnt pathway is a key regulator of its homeostasis and is altered in a large proportion of colon cancers. Protein kinase C (PKC) family of serine/threonine kinases are also involved in colon tumor formation and progression; however, the molecular role played by them in the Wnt pathway, is poorly understood. Reciprocal coimmunoprecipitation and immunofluorescence studies revealed that PKCζ interacts with β-catenin mainly in tumoral colon cells, which overexpressed this PKC isoform. The pharmacological inhibition, the small interference RNA-mediated knockdown of PKCζ or the expression of a dominant-negative form of it in tumoral SW480 cells, blocked in a dose-dependent manner the constitutive transcriptional activity mediated by β-catenin, the cell proliferation and the expression of the Wnt target gene c-myc. Remarkably, the PKCζ stably depleted cells exhibited diminished tumorigenic activity in grafted mice. We show that PKCζ functions in a mechanism that does not involve β-catenin degradation since the effects produced by PKCζ inhibition were also obtained in the presence of proteosome inhibitor and in cells expressing a β-catenin degradation-resistant mutant. It was found that PKCζ activity regulates the nuclear localization of β-catenin since PKCζ inhibition induces a rapid export of β-catenin from the nucleus to the cytoplasm in a Leptomycin B sensitive manner. Taken together, our results indicate that the atypical PKCζ plays an important role in the positive regulation of canonical Wnt pathway.

Journal Article.  7321 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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