PKCalpha mediates TGFbeta-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11.
Growth regulation of epithelial cells is of major concern because most human cancers arise from them. We demonstrated previously a novel signal pathway involving S100C/A11 for high Ca2+-induced growth inhibition of normal human keratinocytes (Sakaguchi, M., M. Miyazaki, M. Takaishi, Y. Sakaguchi, E. Makino, N. Kataoka, H. Yamada, M. Namba, and N.H. Huh. 2003. J. Cell Biol. 163:825-835). This paper addresses a question whether transforming growth factor beta (TGFbeta) shares the pathway with high Ca2+. On exposure of the cells to TGFbeta1, S100C/A11 was phosphorylated, bound to nucleolin, and transferred to the nucleus, resulting in induction of p21WAF1/CIP1 and p15INK4B through activation of Sp1. Protein kinase C alpha (PKCalpha) was shown to phosphorylate 10Thr of S100C/A11, which is a critical event for the signal transduction. The TGFbeta1-induced growth inhibition was almost completely mitigated when PKCalpha activity was blocked or when S100C/A11 was functionally sequestered. These results indicate that, in addition to the well-characterized Smad-mediated pathway, the PKCalpha-S100C/A11-mediated pathway is involved in and essential for the growth inhibition of normal human keratinocytes cells by TGFbeta1.
Sakaguchi
Masakiyo
M
Dept. of Cell Biology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatachou, Okayama 700-8558, Japan.
Miyazaki
Masahiro
M
Sonegawa
Hiroyuki
H
Kashiwagi
Mariko
M
Ohba
Motoi
M
Kuroki
Toshio
T
Namba
Masayoshi
M
Huh
Nam-Ho
NH
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism; D009418:S100 Proteins / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097796:Nucleolin
D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D010750:Phosphoproteins; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D016601:RNA-Binding Proteins; D009418:S100 Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000097796:Nucleolin; C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; C072337:S100A11 protein, human; C496628:PRKCA protein, human