Analysis of the role of MEKK1 as a molecular switch between cell survival and death

MEK kinase 1 (MEKK1) is a serine threonine kinase that mediates cell death and survival pathways. Growth factor receptors activate MEKK1 through the action of small GTP binding proteins this favours cell growth and survival through the c-Jun N-terminal kinase pathway. In contrast, DNA damage induces caspase-3 cleavage of MEKK1 generating a 91 kDa pro-apoptotic fragment. MEKK1 plays a crucial role maintaining the balance between life and death required for homeostasis disruption of this balance results in diseases such as cancer. Increased MEKK1 pro-survival activity is linked to chronic myelogenous leukemia similarly, a deficiency in MEKK1 cleavage is observed in ovarian cancer cells. Our research has shown that MEKK1 mediates the apoptotic activity of tumour necrosis factor apoptosis inducing ligand (TRAIL) through the increased expression of death receptor-4 (DR4). We show that increased expression of DR4 sensitizes the colorectal carcinoma cell line HT29 to TRAIL. In addition, we show that DR4 up-regulation in response to DNA damage occurs through the mediation of the transcription factor NF-kappaB a molecule downstream of MEKK1. This suggests that MEKK1 signalling could potentially be used to sensitize tumour cells to TRAIL, an agent that induces apoptosis in cancer cells but not normal cells. Our research has revealed that the pro-survival molecule AKT blocks MEKK1 induced apoptosis. Increased AKT activity is observed in many types of cancer this means that effectiveness of MEKK1 as an anti-cancer agent depends on the status of AKT.We have demonstrated that MEKK1 effectively activates the mitochondrial death pathway. Expression of MEKK1 activates Bid, Bax and Bak these are members of the Bc1-2 family that mediate the release of pro-apoptotic cytochrome c and Smac/Diablo from the mitochondria. Interestingly, MEKK1 activity releases only Smac/Diablo suggesting their mechanisms of release are distinct from each other. Release of Smac/Diablo seems to play a crucial role in cell death as knockdown of Smac/Diablo blocks MEKK1 induced apoptosis. Other groups have reported that small molecule mimics of Smac/Diablo effectively enhance the apoptotic activity of TRAIL as a result these molecules are currently undergoing clinical trials. Our studies suggest that a mimic of 91 kDa MEKK1 could also activate the intrinsic and extrinsic apoptotic pathways in cancer cells this could sensitize them to cancer specific molecules such as TRAIL.