A sight for sore eyes : assessing oncogenic functions of Hdmx and reactivation of p53 as a potential cancer treatment

Lange, J. de (2012)

Doctoral Thesis

The p53 tumor suppressor protein plays a key role in cancer and its direct or indirect inactivation is an almost universal feature of human tumors. P53 has a central position in the prevention of genomic instability and protection of tumorigenesis. This thesis presents novel studies regarding the role of Hdmx in p53 inactivation during tumorigenesis, as well as the use of specific drugs for p53 reactivation as cancer treatment. Chapter 2 shows that constitutive Hdmx overexpression contributes to the neoplastic transformation of human fibroblasts and embryonic retinoblasts, thereby functionally resembling loss of p53. Chapter 3 establishes the importance of Hdmx as an oncogene in a subset of uveal melanomas. Importantly, the results described in this chapter extend the function of Hdmx beyond p53 inhibition. Chapter 4 evaluates the use of the specific p53 activating drugs Nutlin-3 and RITA in synergy studies as potential therapy for uveal melanoma. Chapter 5 is a more detailed analysis of the cellular responses to RITA. In particular, Chk2 is shown to be an essential mediator of the RITA-induced effects. Chapter 6 is a general discussion of the results presented in this thesis, and their implications for clinical exploitation and future research.

• Uveal melanoma
• Synergy
• RITA
• P53
• Oncogenic transformation
• Nutlin-3
• Hdmx
• Chk2
• Cancer
• Retinoblastoma

• All authors: Lange, J. de
• Supervisor: Dijke, P. ten
• Co-supervisor: Jochemsen, A.G.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2012-05-09