Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction.
A physical and functional interaction between the Ca(2+)-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal regulatory domain of p53 by several in vitro and in vivo approaches: co-immunoprecipitation, affinity chromatography, and far Western blot analysis. The Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. The Mts1 binding to p53 interferes with the DNA binding activity of p53 in vitro and reporter gene transactivation in vivo, and this has a regulatory function. A differential modulation of the p53 target gene (p21/WAF, bax, thrombospondin-1, and mdm-2) transcription was observed upon Mts1 induction in tet-inducible cell lines expressing wild type p53. Mts1 cooperates with wild type p53 in apoptosis induction. Our data imply that the ability of Mts1 to enhance p53-dependent apoptosis might accelerate the loss of wild type p53 function in tumors. In this way, Mts1 can contribute to the development of a more aggressive phenotype during tumor progression.
Department of Molecular Cancer Biology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark. mg@cancer.dk
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M
Grigorian
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S
Andresen
E
E
Tulchinsky
M
M
Kriajevska
C
C
Carlberg
C
C
Kruse
M
M
Cohn
N
N
Ambartsumian
A
A
Christensen
G
G
Selivanova
E
E
Lukanidin
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D002846:Chromatography, Affinity; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53