Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c)
| Autor: | Toshiyuki Sakai, Toshiaki Hitomi, Hoyoku Nishino, Yuuki Takaoka, Youichirou Matsuzaki |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
DNA Complementary Time Factors Proto-Oncogene Proteins c-jun Blotting Western Down-Regulation Cell Cycle Proteins Mitogen-activated protein kinase kinase Transfection Retinoblastoma Protein Cell Line S Phase Mice Cell Line Tumor Genetics Animals Cyclin-Dependent Kinase Inhibitor p18 Humans Enzyme Inhibitors RNA Small Interfering Promoter Regions Genetic Molecular Biology Protein kinase C Protein Kinase C Genes Dominant biology MAP kinase kinase kinase Dose-Response Relationship Drug Cyclin-dependent kinase 4 Cell growth Tumor Suppressor Proteins Cyclin-dependent kinase 2 Cyclin-dependent kinase 3 G1 Phase Enzyme Activation Cancer research biology.protein Tetradecanoylphorbol Acetate Cyclin-dependent kinase 9 Cell Division |
| Zdroj: | Oncogene. 23(31) |
| ISSN: | 0950-9232 |
| Popis: | p18(INK4c), 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 p18(INK4c)-null mice revealed that the p18(INK4c) 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 p18(INK4c) through its promoter, accompanied by the induction of human cancer cell growth. Reduction of p18(INK4c) using small interfering RNA (siRNA) also enhanced cell growth, suggesting that p18(INK4c) is a critical target of TPA. Ro 31-8425, a potent and highly specific PKC inhibitor abrogated the suppressive effect of TPA on p18(INK4c) gene expression. However, the expression of dominant-negative c-Jun (TAM-67) did not inhibit the action of TPA on p18(INK4c). These findings suggest that activation of PKC promotes human cancer cell growth through downregulation of p18(INK4c) 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 p18(INK4c), which is a ubiquitously expressed cyclin-dependent kinase inhibitor. |
| Databáze: | OpenAIRE |
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