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AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

Abstract

The PML protein is best known for its role as a tumor suppressor for acute promyelocytic leukemia. Both PML and the key Wnt signaling regulator AXIN regulate p53-dependent apoptosis in response to DNA damage. However, how the two major tumor suppressors coordinate with each other is unknown, and the molecular components orchestrating the PML-induced apoptosis remain enigmatic. Here we show that AXIN interacts with PML in vivo, and further that AXIN, PML and p53 form a ternary complex. Exposure to genotoxic signals including UV and doxorubicin induces AXIN to enter into the nucleus where it colocalizes with PML in the nuclear bodies. Domain-mapping experiments revealed that the C-terminal region (aa 597–832) of AXIN is responsible for its interaction with PML. AXIN fails to activate p53 in PML−/− cells, and conversely, PML is unable to activate p53 in AXIN-null SNU475 cells. Consistently, knockdown with respective siRNAs revealed that AXIN and PML depend on each other to elevate p53-Ser-46 phosphorylation and to induce apoptosis after treatment with genotoxins. Moreover, we found that dominant-negative mutants of PML blocked AXIN-induced p53 activation, and that AXIN promotes PML sumoylation, a modification necessary for PML functions. Our finding has thus provided a new avenue for understanding the mechanism by which PML activates p53 and exerts its role as a tumor suppressor.

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Acknowledgements

We thank Dr PP Pandolfi for the gift of the wild-type MEF cells and PML−/− MEF cells, Dr Qiao Wu for the RARE luciferase reporter. This work was supported by grants from MOST (nos. 2009CB522200 and 2006AA02A303). This work was also supported by grants from National Natural Science Foundation of China (nos. 30730025, 30921005, 30500273, 30770454, 30970613), the National Basic Research Program of MOST (no. 2007CB914602), the Natural Science Foundation of Fujian Province (nos. 2008J0109 and 2009J06021) and the program for NCET.

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Correspondence to S-C Lin.

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Li, Q., He, Y., Wei, L. et al. AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation. Oncogene 30, 1194–1204 (2011). https://doi.org/10.1038/onc.2010.499

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