The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma.

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TitleThe calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma.
Publication TypeJournal Article
Year of Publication2010
AuthorsLin, J, Yang, Q, Wilder, PT, Carrier, F, Weber, DJ
JournalJ Biol Chem
Volume285
Issue35
Pagination27487-98
Date Published2010 Aug 27
ISSN1083-351X
KeywordsAntigens, CD95, Apoptosis, Carrier Proteins, Caspase 3, Caspase 8, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, Death Domain Receptor Signaling Adaptor Proteins, Down-Regulation, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Apoptosis Proteins, Melanoma, Membrane Potential, Mitochondrial, Multiprotein Complexes, Mutation, Nerve Growth Factors, Phosphorylation, RNA, Messenger, RNA, Neoplasm, RNA, Small Interfering, S100 Proteins, Transcription, Genetic, Tumor Markers, Biological, Tumor Suppressor Protein p53, Ultraviolet Rays
Abstract

The S100B-p53 protein complex was discovered in C8146A malignant melanoma, but the consequences of this interaction required further study. When S100B expression was inhibited in C8146As by siRNA (siRNA(S100B)), wt p53 mRNA levels were unchanged, but p53 protein, phosphorylated p53, and p53 gene products (i.e. p21 and PIDD) were increased. siRNA(S100B) transfections also restored p53-dependent apoptosis in C8146As as judged by poly(ADP-ribose) polymerase cleavage, DNA ladder formation, caspase 3 and 8 activation, and aggregation of the Fas death receptor (+UV); whereas, siRNA(S100B) had no effect in SK-MEL-28 cells containing elevated S100B and inactive p53 (p53R145L mutant). siRNA(S100B)-mediated apoptosis was independent of the mitochondria, because no changes were observed in mitochondrial membrane potential, cytochrome c release, caspase 9 activation, or ratios of pro- and anti-apoptotic proteins (BAX, Bcl-2, and Bcl-X(L)). As expected, cells lacking S100B (LOX-IM VI) were not affected by siRNA(S100B), and introduction of S100B reduced their UV-induced apoptosis activity by 7-fold, further demonstrating that S100B inhibits apoptosis activities in p53-containing cells. In other wild-type p53 cells (i.e. C8146A, UACC-2571, and UACC-62), S100B was found to contribute to cell survival after UV treatment, and for C8146As, the decrease in survival after siRNA(S100B) transfection (+UV) could be reversed by the p53 inhibitor, pifithrin-alpha. In summary, reducing S100B expression with siRNA was sufficient to activate p53, its transcriptional activation activities, and p53-dependent apoptosis pathway(s) in melanoma involving the Fas death receptor and perhaps PIDD. Thus, a well known marker for malignant melanoma, S100B, likely contributes to cancer progression by down-regulating the tumor suppressor protein, p53.

DOI10.1074/jbc.M110.155382
Alternate JournalJ. Biol. Chem.
PubMed ID20587415
PubMed Central IDPMC2930747
Grant ListCA107331 / CA / NCI NIH HHS / United States
GM58888 / GM / NIGMS NIH HHS / United States