Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer.

نویسندگان

  • Susanna Ekholm-Reed
  • Charles H Spruck
  • Olle Sangfelt
  • Frank van Drogen
  • Elisabeth Mueller-Holzner
  • Martin Widschwendter
  • Anders Zetterberg
  • Steven I Reed
چکیده

hCDC4, the gene that encodes the F-box protein responsible for targeting cyclin E for ubiquitin-mediated proteolysis, has been found to be mutated in a number of primary cancers and cancer-derived cell lines. We have observed that functional inactivation of hCDC4 does not necessarily correlate with elevated levels of cyclin E in tumors. Here we show, however, that hCDC4 mutation in primary tumors correlates strongly with loss of cell cycle regulation of cyclin E. Similarly, a breast carcinoma-derived cell line mutated for hCDC4 exhibits cell cycle deregulation of cyclin E, but periodic expression is restored by reintroducing hCDC4 via retroviral transduction. Conversely, small interfering RNA-mediated silencing of hCdc4 deregulates cyclin E with respect to the cell cycle. These results indicate that hCdc4 function is an absolute prerequisite for cell cycle regulation of cyclin E levels, and loss of hCdc4 function is sufficient to deregulate cyclin E.

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عنوان ژورنال:
  • Cancer research

دوره 64 3  شماره 

صفحات  -

تاریخ انتشار 2004