Cross, J.R.; (2006) Regulation of the pro-apoptotic protein Bax. Doctoral thesis , University of London.

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Abstract

Apoptosis is essential for correct development and tissue homeostasis of multi-cellular organisms as well as providing a critical safety mechanism to remove unwanted and damaged cells throughout life. Apoptosis is also relevant to human pathologies: many cancers acquire lesions in apoptotic pathways whilst inappropriate activation of apoptosis occurs in degenerative disease. This thesis studies the regulation and function of a key regulator of apoptosis and mitochondrial dysfunction, the Bcl-2 family member, Bax. Bax is shown to be a cytoplasmic protein that, upon activation, rapidly translocates into mitochondrially-associated foci. The timing and possible causes of Bax activation have been studied. Live cell video microscopy reveals that this is a rapid and co-ordinated process and is accompanied by loss of the mitochondrial membrane potential. Two viral proteins, El B 19k from Adenovirus and BHRF1 from Epstein Bar Virus, are shown to block Bax activation at different steps. Using these proteins it is shown that changes in mitochondrial ultrastructure occur prior to Bax activation. In the second part of this thesis, a structure / function analysis of the Bax protein leads to the identification of a novel mutation that promotes its activation. Subsequently, this mutation is used, in combination with El B 19k, in a proteomic strategy to isolate and identify candidate Bax interacting proteins at a critical step in the protein's activation. The results of this, and a similar screen with another Bcl-2 family protein, Bcl-XL, are reported. The data set contains known interacting proteins and proteins previously implicated in apoptosis control. In addition a range of metabolic and transport proteins not previously implicated in the control of Bcl-2 family proteins are identified and their relevance discussed.

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