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    Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids. 
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    Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids.

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    Published version (4.404Mb)
    Volume
    35
    Pagination
    396 - 406
    DOI
    10.1093/carcin/bgt313
    Journal
    Carcinogenesis
    Issue
    2
    Metadata
    Show full item record
    Abstract
    Protein kinase C iota (PKCι), a serine/threonine kinase required for cell polarity, proliferation and migration, is commonly up- or downregulated in cancer. PKCι is a human oncogene but whether this is related to its role in cell polarity and what repertoire of oncogenes acts in concert with PKCι is not known. We developed a panel of candidate oncogene expressing Madin-Darby canine kidney (MDCK) cells and demonstrated that H-Ras, ErbB2 and phosphatidylinositol 3-kinase transformation led to non-polar spheroid morphogenesis (dysplasia), whereas MDCK spheroids expressing c-Raf or v-Src were largely polarized. We show that small interfering RNA (siRNA)-targeting PKCι decreased the size of all spheroids tested and partially reversed the aberrant polarity phenotype in H-Ras and ErbB2 spheroids only. This indicates distinct requirements for PKCι and moreover that different thresholds of PKCι activity are required for these phenotypes. By manipulating PKCι function using mutant constructs, siRNA depletion or chemical inhibition, we have demonstrated that PKCι is required for polarization of parental MDCK epithelial cysts in a 3D matrix and that there is a threshold of PKCι activity above and below which, disorganized epithelial morphogenesis results. Furthermore, treatment with a novel PKCι inhibitor, CRT0066854, was able to restore polarized morphogenesis in the dysplastic H-Ras spheroids. These results show that tightly regulated PKCι is required for normal-polarized morphogenesis in mammalian cells and that H-Ras and ErbB2 cooperate with PKCι for loss of polarization and dysplasia. The identification of a PKCι inhibitor that can restore polarized morphogenesis has implications for the treatment of Ras and ErbB2 driven malignancies.
    Authors
    Linch, M; Sanz-Garcia, M; Rosse, C; Riou, P; Peel, N; Madsen, CD; Sahai, E; Downward, J; Khwaja, A; Dillon, C
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/15767
    Collections
    • Centre for Tumour Biology [355]
    Language
    eng
    Licence information
    Creative Commons Attribution‐NonCommercial License
    Copyright statements
    2013. the authors
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