Autor: |
Ingram L; Laboratory of Cancer Biology, Department of Clinical Pharmacology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford, OX3 7DQ, UK., Munro S, Coutts AS, La Thangue NB |
Jazyk: |
angličtina |
Zdroj: |
Cell death and differentiation [Cell Death Differ] 2011 Jan; Vol. 18 (1), pp. 122-32. Date of Electronic Publication: 2010 Jun 18. |
DOI: |
10.1038/cdd.2010.70 |
Abstrakt: |
E2F activity is negatively regulated by retinoblastoma protein (pRb) through binding to the E2F-1 subunit. Within the E2F heterodimer, DP proteins are E2F partner subunits that allow proper cell cycle progression. In contrast to the other DP proteins, the newest member of the family, DP-4, downregulates E2F activity. In this study we report an unexpected role for DP-4 in regulating E2F-1 activity during the DNA damage response. Specifically, DP-4 is induced in DNA-damaged cells, upon which it binds to E2F-1 as a non-DNA-binding E2F-1/DP-4 complex. Consequently, depleting DP-4 in cells re-instates E2F-1 activity that coincides with increased levels of chromatin-bound E2F-1, E2F-1 target gene expression and associated apoptosis. Mutational analysis of DP-4 highlighted a C-terminal region, outside the DNA-binding domain, required for the negative control of E2F-1 activity. Our results define a new pathway, which acts independently of pRb and through a biochemically distinct mechanism, involved in negative regulation of E2F-1 activity. |
Databáze: |
MEDLINE |
Externí odkaz: |
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