title: Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.
abstract: In response to various cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes. However, the full picture of the p53 downstream pathway still remains to be elucidated. Here we identified cystatin C, a major inhibitor of cathepsins, as a novel p53 target. In response to DNA damage, activated p53 induced cystatin C expression through p53 binding sequence in the first intron. We showed that cathepsin L activity was decreased in HCT116 p53(+/+) cells after adriamycin treatment, but not in HCT116 p53(-/-) cells. We also found that knockdown of cystatin C reduced adriamycin-induced caspase-3 activation. Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer. Our findings revealed an important role of the p53-cystatin C pathway in human carcinogenesis.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
authors.forename: Jinichi
authors.initials: J
authors.lastname: Mori
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
authors.forename: Chizu
authors.initials: C
authors.lastname: Tanikawa
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Funauchi
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
authors.forename: Paulisally Hau Yi
authors.initials: PH
authors.lastname: Lo
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.|Departments of Medicine and Surgery, and Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D056668:Cathepsin L / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D016384:Consensus Sequence; D055316:Cystatin C / Q000502:physiology*; D004249:DNA Damage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C525030:CST3 protein, human; D055316:Cystatin C; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C534281:CTSL protein, human; D056668:Cathepsin L
keywords: Breast cancer; cathepsin; cystatine; p53; tumor suppressor