PML Is Required For UV-induced Axin-mediated Cell Death

Axin (Axis inhibitor) is a scaffold protein which plays important roles in multiple signal-transduction pathways. In the Wnt signaling pathway, Axin stimulates degradation ofβ-catenin by forming a large multimeric protein complex with APC, GSK-3βandβ-catenin. In JNK signaling, Axin activates JNK by directly binding to MEKK1 or MEKK4. In TGF-βsignaling, Axin enhances the transcriptional activity of Smad3. Besides, Axin regulates the transcriptional activity of p53 by forming a protein complex with p53 and HIPK2. These different signaling pathways control cellular processes, including cell proliferation, differentiation, transformation, apoptosis and cell cycle arrest.PML, an important tumor suppressor, was originally cloned and identified from APL patient. It locates on the PML-NB, which is a multimetric complex containing SUMO-1, Sp100, Sp140, CBP, BLM, Daxx, pRB, p53 and so on. In APL patients, PML fuses with RARα, and the resulting fusion protein dimerizes with PML and interfere with the formation of nuclear body, leading to the disorder of survival, proliferation, differentiation of normal cell and tumor suppression.It has been shown that both Axin and PML are tumor suppressors and are involved in p53-induced apoptosis, but the relationship between them is not clear. In this study, taking advantage of the methods of biochemistry, molecular biology and cell biology, I focused on the relationship between Axin and PML, and discovered that PML plays an important role in Axin induced cell death. (1) UV irradiation stimulates redistribution of Axin from cytoplasm to PML-NB in the nucleus; (2) Axin interacts with PML; (3) PML is required for Axin-mediated p53 activation, and this activation can be blocked by its dominate forms and siRNA; (4) Both PML and Axin are involved in UV-induced cell death; (5) PML is required for Axin-induced cell death, both dominant negative forms and siRNA of PML can block the process. In conclusion, all data give evidence of the effect of PML on UV-induced, Axin-mediated cell death, as sheds a new light on our understanding of Axin.