AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation.
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.
Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, Fujian Laboratory for Cancer Biology, School of Life Sciences, Xiamen University, Fujian, China.
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D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D060466:Axin Protein; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins