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Activation of protein kinase C promotes human cancer cell growth through downregulation of p18INK4c

Oncogene volume 23, pages 5409–5414 (2004)Cite this article

Abstract

p18INK4c, a member of INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the cyclin D-cyclin-dependent kinase 4/6 complexes which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. Several recent studies using p18INK4c-null mice revealed that the p18INK4c plays an important role in cell proliferation and tumor development. We report here that 12-O-tetradecanoylphorbol-13-acetate (TPA), widely used as a protein kinase C (PKC) activator, suppresses the expression of p18INK4c through its promoter, accompanied by the induction of human cancer cell growth. Reduction of p18INK4c using small interfering RNA (siRNA) also enhanced cell growth, suggesting that p18INK4c is a critical target of TPA. Ro 31-8425, a potent and highly specific PKC inhibitor abrogated the suppressive effect of TPA on p18INK4c gene expression. However, the expression of dominant-negative c-Jun (TAM-67) did not inhibit the action of TPA on p18INK4c. These findings suggest that activation of PKC promotes human cancer cell growth through downregulation of p18INK4c in an AP-1 activation-independent manner. These results suggest that the accelerated cellular proliferation of some human tumors caused by enhanced PKC activity at least partially involves the suppression of p18INK4c, which is a ubiquitously expressed cyclin-dependent kinase inhibitor.

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Acknowledgements

This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan, a grant (H11-Seikatsu-018) for Research on Environmental Health from the Ministry of Health, Labor and Welfare of Japan and the SRF Grant for Biomedical Research.

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Authors and Affiliations

  1. Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Youichirou Matsuzaki, Yuuki Takaoka, Toshiaki Hitomi & Toshiyuki Sakai

  2. Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Hoyoku Nishino

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  1. Youichirou Matsuzaki
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Correspondence to Toshiyuki Sakai.

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Matsuzaki, Y., Takaoka, Y., Hitomi, T. et al. Activation of protein kinase C promotes human cancer cell growth through downregulation of p18INK4c. Oncogene 23, 5409–5414 (2004). https://doi.org/10.1038/sj.onc.1207702

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