Indentification of MNDA modifications and domains involved in regulation of apoptosis

点击翻译按钮获取中文摘要

Different stress and/or the damaging of cells can trigger an intracellular mechanism that induces cell death. This mechanism is called "apoptosis". It is an important mechanism to get rid of damaged cells which, otherwise, could induce tissue damage or cancer. We previously defined a novel pathway initiating in the nucleus and signalling to the mitochondria that regulates apoptosis of myeloid and granulocytic cells. The central protein involved in this newly identified signalling is the Myeloid Nuclear Differentiation Antigen (MNDA). When MNDA is relocated from the nucleus to the cytoplasm and the membrane of mitochondria, it interacts with and promotes the degradation of the anti-apoptotic factor MCL-1. This relocation of MNDA correlates with a variation of MNDA phosphorylation, which results from the activity of a yet unidentified enzyme (kinase or phosphatase). Since the modification MNDA phosphorylation follows an extracellular stress, we will look into extracellular signalling pathways to identify pathway(s) affecting MNDA phosphorylation. The importance of MNDA phosphorylation pattern in its relocation to the cytoplasm will be questioned by the mutation of MNDA protein. The identification of the enzyme(s) involved in MNDA phosphorylation will be attempted and the mutation of MNDA will be made to avoid the variation of phosphorylation. Then, the relocation of MNDA and influence of MNDA on apoptosis will be tested. Thus, we aim to identify how the function of MNDA is controlled and regions of MNDA important for the control of apoptosis. There are only few examples of such nuclear to mitochondria signalling. This novel field of investigation is growing rapidly and it is attracting more and more interest due to the importance of the control of apoptosis regulation.