Abstract |
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.
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Authors | Youichirou Matsuzaki, Yuuki Takaoka, Toshiaki Hitomi, Hoyoku Nishino, Toshiyuki Sakai |
Journal | Oncogene
(Oncogene)
Vol. 23
Issue 31
Pg. 5409-14
(Jul 08 2004)
ISSN: 0950-9232 [Print] England |
PMID | 15107819
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CDKN2C protein, human
- Cdkn2c protein, mouse
- Cell Cycle Proteins
- Cyclin-Dependent Kinase Inhibitor p18
- DNA, Complementary
- Enzyme Inhibitors
- Proto-Oncogene Proteins c-jun
- RNA, Small Interfering
- Retinoblastoma Protein
- Tumor Suppressor Proteins
- Protein Kinase C
- Tetradecanoylphorbol Acetate
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Topics |
- Animals
- Blotting, Western
- Cell Cycle Proteins
(metabolism)
- Cell Division
- Cell Line
- Cell Line, Tumor
- Cyclin-Dependent Kinase Inhibitor p18
- DNA, Complementary
(metabolism)
- Dose-Response Relationship, Drug
- Down-Regulation
- Enzyme Activation
- Enzyme Inhibitors
(pharmacology)
- G1 Phase
- Genes, Dominant
- Humans
- Mice
- Promoter Regions, Genetic
- Protein Kinase C
(metabolism)
- Proto-Oncogene Proteins c-jun
(metabolism)
- RNA, Small Interfering
(metabolism)
- Retinoblastoma Protein
(metabolism)
- S Phase
- Tetradecanoylphorbol Acetate
- Time Factors
- Transfection
- Tumor Suppressor Proteins
(metabolism)
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