Obermueller, Frank Michael; (1998) The role of the tumour suppressor p53 in cooperation with Ras and Raf oncogenes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

To study the molecular mechanisms of oncogene cooperation, rat Schwann cells were used in which oncogenic Ras or Raf alone cause a cell cycle arrest, whereas cooperating oncogenes lead to transformation (Ridley et al., 1988; Lloyd et al., 1997). This model system was used to search for cooperating oncogenes and to investigate the underlying biochemical mechanisms of oncogene cooperation. Interestingly, mutants of the tumour suppressor p53 efficiently cooperate with oncogenic Ras or Raf to transform Schwann cells. This result prompted me to further investigate the role of p53 in Schwann cells expressing an inducible activated Raf (ARafER). Activation of ARafER led to the induction of the cell cycle inhibitor p21WAF1/Cip1. induction of p21WAF1/Cip1 is p53-dependent, since dominant negative mutants of p53 abolish this induction and subsequently the G1 cell cycle arrest. The pathway leading to the p53-dependent induction of p21WAF1/Cip1 by activated Raf was investigated by addressing the possible role of the MAP-kinase pathway. The contribution of MAP-kinase kinase and MAP-kinase in the signalling pathway triggering the G1 cell cycle arrest were examined using dominant negative and constitutively active mutants as well as a specific chemical inhibitor. My results indicate that MAP-kinase kinase is necessary for p21WAF1/Cip1 induction in Schwann cells. The contribution of the JNK-kinase pathway in the Raf-initiated cell cycle arrest was addressed.

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