Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells.
S100 calcium-binding proteins such as S100B are elevated in primary malignant melanoma and are used as markers for this and numerous other cancers. Wild-type p53 protein levels are relatively low in these cancer cells (i.e. when compared with cells without S100B) but are elevated when RNA antisense to S100B is introduced. This result implicates S100B in the down-regulation of p53 and is consistent with the large decreases in p53 protein levels observed previously in transient co-transfections of p53 and S100B (Lin, J., Blake, M., Tang, C., Zimmer, D., Rustandi, R. R., Weber, D. J., and Carrier, F. (2001) J. Biol. Chem. 276, 35037-35041). Down-regulation of p53 in primary malignant melanoma cells is likely the result of a direct interaction with S100B, which was observed by co-immunoprecipitation experiments. Furthermore, p53 binds regions of the S100B promoter, one of which matches the 20-nucleotide p53-binding consensus DNA sequence perfectly. Therefore, when p53 levels increase, it contributes to its own demise by up-regulating the transcription of S100B as part of a negative feedback loop. This is analogous to what is found for another protein that down-regulates p53, namely hdm2 (human double mutant 2).
Lin
Jing
J
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Yang
Qingyuan
Q
Yan
Zhe
Z
Markowitz
Joseph
J
Wilder
Paul T
PT
Carrier
France
F
Weber
David J
DJ
D001665:Binding Sites / Q000235:genetics; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007163:Immunosorbent Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000737:chemistry; D009414:Nerve Growth Factors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D000097642:GADD45 Proteins
D015500:Chloramphenicol O-Acetyltransferase; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C579160:S100B protein, human