Sorensen, Troels Seyffart; (1996) Characterisation of DP-1. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The transcription factor DRTF1/E2F regulates genes required for cell cycle progression and occupies a central role in the control of cellular proliferation by integrating cell cycle machinery with transcription. DRTF1/E2F transcriptional activity is regulated in part by the binding of the tumour suppressor pRb which is mutationally inactivated in a large range of human cancers. Mutations in the p53 tumour suppressor gene are the most frequently observed genetic alterations in human neoplasia. Recent data suggests that the p53 gene product controls a cell cycle checkpoint responsible for maintaining the integrity of the genome, although the exact mechanism by which this occurs is still unclear. The DNA binding activity of DRTF1/E2F is believed to be a heterodimer composed of one of each of the DP- and E2F- polypeptide families. I present evidence that one member, DP-1, can exist in a hypo- or hyper-phosphorylated state in vivo, which in turn correlates with altered DRTF1/E2F affinity for its DNA binding site. Data indicates that the different phosphorylation state may affect DP-I's ability to heterodimerise with partners such as E2F-1 and E2F-5, an event essential for high affinity DNA binding and subsequent transcriptional trans-activation. These results potentially define a new level of control for DRTF1/E2F in which its DNA binding activity is modulated by cell cycle-regulated phosphorylation events on DP-1. Also presented is evidence suggesting that one phosphoform of DP-1 can form an in vivo complex with p53 and that p53 can repress the DNA binding activity of DP- 1/E2F-1 heterodimers. These results contribute to the establishment of DP-1 as a common cellular target in two distinct and independent pathways of growth control mediated through the activities of the pRb and p53 tumour suppressor proteins. The integration of p53 with DP-1 and the consequent regulation of DRTF1/E2F DNA binding activity defines novel potential pathway through which p53 can influence cell cycle progression.

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