Visit our Expo - Redox and Inflammation signaling 2012

Session II : Receptor signaling and G proteins Poster II, 28
S100C/A11, an essential element of the signal transduction of TGFb-induced growth
suppression and a potential target for therapy against hyper-proliferative human
diseases.
Nam-ho Huh, Eiichi Makino, and Masakiyo Sakaguchi.
Department of Cell Biology, Okayama University Graduate School of Medicine,
Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan E-mail :
namu@md.okayama-u.ac.jp
TGFb is known to be a potent growth suppressor to epithelial cells, including epidermal
keratinocytes. We have demonstrated that S100C/A11, an EF-hand-type Ca++-binding
protein, plays a critical role for the signal transduction. On exposure of normal human
keratinocytes to TGFb, S100C/A11 was specifically phosphorylated at 10Thr by PKCa. The
phosphorylation facilitated the binding of S100C/A11 to nucleolin, resulting in nuclear
translocation of S100C/A11. In nuclei, S100C/A11 liberated Sp1/3 from nucleolin. The
resulting free Sp1/3 transcriptionally activated p21(WAF1), a representative negative
regulator of cell growth. The new pathway involving S100C/A11 was shown to be
indispensable for the growth suppression by TGFb together with the well-known Smadmediated
pathway.
Since the phosphorylated N-terminal domain of S100C/A11 was demonstrated to be
critical for exhibiting the function described above, we introduced into cells a peptide
composed of N-terminal 19 amino acids flanked by HIV-TAT protein transduction domain.
The peptide induced apoptotic cell death in a number of human normal and tumor cells. The
induction of apoptotic cell death was apparently independent of p53, p21(WAF1), and
caspase activity, but treatment with the peptide resulted in partial translocation of apoptosisinducing
factor (AIF) from the cytoplasm to nuclei. These results indicate that the peptide
may lead to the establishment of a new molecular target for the treatment of human cancer
and other hyper-proliferative diseases.
References: J Cell Biol 24;163(4):825-35, 2003; J Cell Biol 164(7):979-84, 2004; J Mol
Med 82(9):612-20, 2004; Proc Natl Acad Sci USA. 102(39):13921-6, 2005.
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