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Deregulation of E2f-1 and chemosensitivity.

Hampel, C.; (2004) Deregulation of E2f-1 and chemosensitivity. Doctoral thesis , University of London. Green open access

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Abstract

The E2F transcription factors are key components of the retinoblastoma tumour suppressor pathway which control the progression from G1 to S phase in the cell cycle and regulate the transcription of proteins required for S-phase entry and DNA synthesis. Deregulation of E2F-1 expression results in the loss of control of normal cell cycle progression. Aberrations of the retinoblastoma pathway have been reported in most human cancers. Alteration in cell cycle regulation may alter the activity of anti-cancer drugs. An increase in E2F-1 activity and transcription of E2F-regulated genes potentially influences the cellular sensitivity to chemotherapeutic agents. This study aimed to investigate the pattern, mechanism and potential inhibition of E2F-1 interactions with chemotherapeutic agents. Initial experiments performed on an HT1080 cell line stably overexpressing E2F-1 suggested a role in resistance to several DNA interactive agents, in particular the minor groove binding alkylating agent BGIII21. However, further characterisation identified the HT1080 transfectants to be CHO cell lines. Experiments using an inducible E2F-1 cell line showed increased expression of E2F-1 to have a minimal effect on chemosensitivity to BGIII21. A decrease in chemosensitivity was observed in response to BGIIII21 in CHO cells. NER, homologous recombination or mismatch repair deficiency were not found to be the underlying causes for resistance in CHO cells. Experiments using E2F-1 inhibitory peptides, despite exhibiting marked inter-experimental variations, suggested an inverse correlation between endogenous E2F-1 expression level and peptide activity. Further, cell cycle analysis showed the E2F-1 inhibitory peptides to cause G1 arrest or apoptosis in leukemic cell lines. In conclusion, inhibition of E2F-1 activity through peptides was found to be a valuable but unreliable tool to influence the effect of chemotherapeutic agents on cells expressing increased levels of E2F-1 due to persistent variations in factors affecting peptide activity.

Type: Thesis (Doctoral)
Title: Deregulation of E2f-1 and chemosensitivity.
Identifier: PQ ETD:602560
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest The copyright of this th esis re sts with th e author and no quotation fromit or inform ation derived from it m ay be published without the prior written co nsent of the author.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: http://discovery.ucl.ac.uk/id/eprint/1446635
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