Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53.
Dickkopf-1 (Dkk-1), a secreted glycoprotein, has been found to be necessary and sufficient for inducing amphibian head formation. Interestingly, the mechanism by which Dkk-1 does this is the ability of Dkk-1 to antagonize the Wnt signaling pathway. Wnt, itself a proto-oncoprotein, can promote cell proliferation and transformation when mutated or overexpressed, leading to tumor formation. p53 is a tumor suppressor and loss of p53 function accelerates mammary tumorigenesis by Wnt. In this study, we found that Dkk-1 is induced by wild-type p53 but not mutant p53(R249S). In addition, DNA damage upregulates Dkk-1 in cell lines that harbor an endogenous wild-type p53 gene but not in cell lines that are p53-null or harbor an endogenous mutant p53 gene. We also found a potential p53 responsive element located approximately 2100 nucleotides upstream of the Dkk-1 transcription start site and we show that p53 binds specifically to this element both in vitro and in vivo. Furthermore, we have established several cell lines derived from H1299 lung carcinoma and U118 glioma cells that inducibly express Dkk-1 under a tetracycline-regulated promoter. We found that Dkk-1 has no effect on proliferation of cells that are not transformed by Wnt. Taken together, these results suggest that Dkk-1 may mediate p53 tumor suppression by antagonizing the Wnt signaling pathway.
Wang
J
J
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta 30912, USA.
Shou
J
J
Chen
X
X
D002166:Camptothecin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C501128:dkk1b protein, zebrafish; D002166:Camptothecin