Indentification of MNDA modifications and domains involved in regulation of apoptosis

不同的应激和/或细胞损伤可触发细胞内机制，诱导细胞死亡。这种机制被称为“细胞凋亡”。这是清除受损细胞的重要机制，否则可能导致组织损伤或癌症。我们之前定义了一种新的途径，从细胞核开始，信号传导到线粒体，调节髓细胞和粒细胞的凋亡。参与这种新发现的信号传导的中心蛋白是髓样核分化抗原（MNDA）。当MNDA从细胞核迁移到细胞质和线粒体膜时，它与抗凋亡因子MCL-1相互作用并促进其降解。MNDA的这种重新定位与MNDA磷酸化的变化有关，这是由一种尚未确定的酶（激酶或磷酸酶）的活性引起的。由于修饰MNDA磷酸化遵循细胞外应激，我们将研究细胞外信号通路，以确定影响MNDA磷酸化的途径。随着MNDA蛋白的突变，其磷酸化模式在细胞质重新定位中的重要性将受到质疑。将尝试鉴定参与MNDA磷酸化的酶，并对MNDA进行突变以避免磷酸化的变异。然后，我们将检测MNDA的重新定位以及MNDA对细胞凋亡的影响。因此，我们的目标是确定MNDA的功能是如何被控制的，以及MNDA对细胞凋亡控制的重要区域。这种核到线粒体信号传递的例子很少。由于细胞凋亡调控的重要性，这一新兴的研究领域正在迅速发展，并引起了越来越多的关注。

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.