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      Cystatin C as a p53‐inducible apoptotic mediator that regulates cathepsin L activity

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          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.

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          Most cited references56

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          The first 30 years of p53: growing ever more complex.

          Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.
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            Definition of a consensus binding site for p53.

            Recent experiments have suggested that p53 action may be mediated through its interaction with DNA. We have now identified 18 human genomic clones that bind to p53 in vitro. Precise mapping of the binding sequences within these clones revealed a consensus binding site with a striking internal symmetry, consisting of two copies of the 10 base pair motif 5'-PuPuPuC(A/T)(T/A)GPyPyPy-3' separated by 0-13 base pairs. One copy of the motif was insufficient for binding, and subtle alterations of the motif, even when present in multiple copies, resulted in loss of affinity for p53. Mutants of p53, representing each of the four "hot spots" frequently altered in human cancers, failed to bind to the consensus dimer. These results define the DNA sequence elements with which p53 interacts in vitro and which may be important for p53 action in vivo.
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              The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.

              To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women 10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.
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                Author and article information

                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                04 March 2016
                March 2016
                : 107
                : 3 ( doiID: 10.1111/cas.2016.107.issue-3 )
                : 298-306
                Affiliations
                [ 1 ] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical ScienceThe University of Tokyo Minato TokyoJapan
                [ 2 ] Departments of Medicine and Surgery, and Center for Personalized TherapeuticsThe University of Chicago Chicago IllinoisUSA
                Author notes
                [*] [* ] Correspondence

                Koichi Matsuda, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4‐6‐1, Shirokanedai, Minato, Tokyo 108‐8639, Japan.

                Tel: +81‐3‐5449‐5376; Fax: +81‐3‐5449‐5123;

                E‐mail: koichima@ 123456ims.u-tokyo.ac.jp

                Article
                CAS12881
                10.1111/cas.12881
                4814261
                26757339
                4d05d409-76c3-4b7e-9fe0-61e0ef85f11d
                © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 30 July 2015
                : 25 December 2015
                : 03 January 2016
                Page count
                Pages: 9
                Funding
                Funded by: Japan Society for the Promotion of Science
                Funded by: Ministry of Education, Culture, Sports, Science and Technology, Japan
                Funded by: Ministry of Health, Labor and Welfare, Japan
                Funded by: Tokyo Biochemical Research Foundation
                Categories
                Original Article
                Original Articles
                Cell, Molecular, and Stem Cell Biology
                Custom metadata
                2.0
                cas12881
                March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.5 mode:remove_FC converted:30.03.2016

                Oncology & Radiotherapy
                breast cancer,cathepsin,cystatine,p53,tumor suppressor
                Oncology & Radiotherapy
                breast cancer, cathepsin, cystatine, p53, tumor suppressor

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