Notch1-dependent regulation of p27 determines cell fate in colorectal cancer

  • Authors:
    • Nevyana R. Hristova
    • Katrin E. Tagscherer
    • Anne Fassl
    • Juergen Kopitz
    • Wilfried Roth
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  • Published online on: October 17, 2013     https://doi.org/10.3892/ijo.2013.2140
  • Pages: 1967-1975
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Abstract

Enhanced Notch signaling contributes to uncontrolled cell growth and cell death resistance in cancer. Here, we demonstrate that in colorectal carcinoma cells the Notch1-dependent activation of cell cycle and proliferation is mediated by repression of the cyclin-dependent kinase inhibitor (CDKI) p27. The half-life of p27 significantly increased after siRNA‑mediated knockdown of Notch1. Notch1 depletion altered the transcription of SKP2, KPC1 and KPC2, which are E3-ubiquitin ligase subunits targeting p27 for proteasomal degradation in the nucleus and the cytoplasm, respectively. As a consequence, the levels of p27 in both cellular fractions were elevated upon Notch1 knockdown. Importantly, the downregulation of Notch1 significantly sensitized colorectal cancer cells to chemotherapy and ionizing radiation. Our findings support an important role of p27 in Notch1-dependent oncogenic signaling and suggest that Notch1 is a promising target for an experimental therapy of colorectal carcinoma.
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December 2013
Volume 43 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Hristova, N.R., Tagscherer, K.E., Fassl, A., Kopitz, J., & Roth, W. (2013). Notch1-dependent regulation of p27 determines cell fate in colorectal cancer. International Journal of Oncology, 43, 1967-1975. https://doi.org/10.3892/ijo.2013.2140
MLA
Hristova, N. R., Tagscherer, K. E., Fassl, A., Kopitz, J., Roth, W."Notch1-dependent regulation of p27 determines cell fate in colorectal cancer". International Journal of Oncology 43.6 (2013): 1967-1975.
Chicago
Hristova, N. R., Tagscherer, K. E., Fassl, A., Kopitz, J., Roth, W."Notch1-dependent regulation of p27 determines cell fate in colorectal cancer". International Journal of Oncology 43, no. 6 (2013): 1967-1975. https://doi.org/10.3892/ijo.2013.2140