Helgason, Guđmundur Vignir
E2F1 induction following DNA damage and oncogene activation.
PhD thesis, University of Glasgow.
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The transcription factor E2F1, a critical target of the tumour suppressor pRb, is deregulated in most human cancers. Oncogenes have been shown to deregulate E2F1 through inhibition of pRB and deregulation of E2F1 is an event that occurs in most human cancers. The essential role of E2F1 in apoptosis is well documented and deregulated E2F1 can enhance drug induced death. E2F1 is induced by various chemotherapeutic drugs and this induction, in addition with oncogenic stress, contributes to increased chemosensitivity.
Cells expressing the adenovirus early region 1A (E1A) oncogene have been used as a tool to identify cellular regulatory pathways that modulate chemosensitivity. E1A sensitises cells to the induction of apoptosis by diverse stimuli, including many chemotherapeutic drugs. These E1A activities are mediated through binding the RB family proteins (pRb, p107 and p130) and via the E1A N-terminal domain that interacts with different cellular protein complexes including the p300/CBP transcriptional activator and p400/TRRAP chromatin-remodeling complex.
The results presented here illustrate novel mechanisms of E2F1 induction both by oncogenes and chemotherapeutic drugs. Two minimal domains of E2F1 are described that are induced following DNA damage via mechanism(s) not previously identified. In addition, data are presented which show that E1A expression not only deregulates E2F1, but also elevates E2F1 levels. E1A is dependent on interaction with RB protein to induce E2F1 levels and this elevation contributes to cell death. Using previously described protein binding deficient truncations of E1A, we demonstrate that E1A binding to the p400/TRRAP protein complex is also critical for the induction of E2F1. E1A binding to p400/TRRAP was also critical in sensitizing these cells to drug induced apoptosis. Suppression of p400 using siRNA had similar affect on E2F1 induction and caused an increase in drug sensitivity indicating that E1A inhibits p400 function.
These results contribute to the understanding of how activation of the E2F1 pathway may be targeted therapeutically to enhance chemotherapy-induced tumour cell death.
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