Introduction of an N-terminal peptide of S100C/A11 into human cells induces apoptotic cell death.
S100 proteins belong to the EF-hand Ca2+-binding protein family and are involved in the regulation of a variety of cellular processes. Individual S100 proteins are expressed in cell- and tissue-specific manners, and functional deterioration of S100 proteins leads to a number of human diseases, including cancer. We previously demonstrated that S100C/A11 was translocated to nuclei and inhibited DNA synthesis in human keratinocytes when exposed to high Ca2+. In the present study we examined the effects of synthetic partial peptides of S100C/A11 on human carcinoma cell lines. Only an N-terminal peptide with 19 amino acid residues (MAK19) showed cytotoxicity to the cell lines in dose- and time-dependent manners when introduced into cells by flanking the HIV-TAT protein transduction domain (TAT-MAK19). Pulse field electrophoresis revealed that DNA of the treated cells was partially degradated. Annexin V, a marker of cellular apoptosis, was detected in the cells treated with TAT-MAK19 by immunostaining and flow cytometry. The induction of apoptotic cell death was apparently independent of p53, p21WAF1/CIP1, and caspase activity, but treatment with TAT-MAK19 resulted in partial translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. These results indicate that MAK19 induces apoptosis in human cell lines and may therefore lead to the establishment of a new molecular target for the treatment of human cancer.
Makino
Eiichi
E
Department of Dermatology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatachou, 700-8558, Okayama, Japan.
Sakaguchi
Masakiyo
M
Iwatsuki
Keiji
K
Huh
Nam-ho
NH
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004261:DNA Replication / Q000187:drug effects; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000473:pathology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D009418:S100 Proteins / Q000737:chemistry / Q000494:pharmacology*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015696:Gene Products, tat; D010446:Peptide Fragments; D009418:S100 Proteins; C072337:S100A11 protein, human