Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c).
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.
Matsuzaki
Youichirou
Y
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Takaoka
Yuuki
Y
Hitomi
Toshiaki
T
Nishino
Hoyoku
H
Sakai
Toshiyuki
T
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase; D005799:Genes, Dominant; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493971:CDKN2C protein, human; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate