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      SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer

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      Author
      Sayan, A. E.
      Griffiths, T. R.
      Pal, R.
      Browne G. J.
      Ruddick, A.
      Yagci, T.
      Edwards, R.
      Mayer, N. J.
      Qazi, H.
      Goyal, S.
      Fernandez, S.
      Straatman, K.
      Jones G. D. D.
      Bowman, K. J.
      Colquhoun, A.
      Mellon, J. K.
      Kriajevska, M.
      Tulchinsky, E.
      Date
      2009
      Source Title
      Proceedings of the National Academy of Sciences of the United States of America
      Print ISSN
      0027-8424
      Publisher
      National Academy of Sciences
      Volume
      106
      Issue
      35
      Pages
      14884 - 14889
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P = 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV- and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival.
      Keywords
      Cisplatin
      DNA
      Iron binding protein
      Selenium
      Sip1 protein
      Transcription factor Snail
      Unclassified drug
      Uvomorulin
      Permalink
      http://hdl.handle.net/11693/22640
      Published Version (Please cite this version)
      http://dx.doi.org/10.1073/pnas.0902042106
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