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

Jing Lin1, Qingyuan Yang2, Paul T Wilder3

  • 1Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Maryland 21201.

The Journal of Biological Chemistry
|July 1, 2010
PubMed

Insights

The S100B protein, a marker for malignant melanoma, suppresses the tumor suppressor protein p53. Inhibiting S100B activates p53, promoting cancer cell death via the Fas death receptor pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The S100B protein is a known marker for malignant melanoma.
  • The interaction between S100B and the p53 protein in melanoma requires further investigation.
  • Understanding this interaction may reveal new therapeutic targets for melanoma.

Purpose of the Study:

  • To investigate the functional consequences of the S100B-p53 protein interaction in malignant melanoma.
  • To determine if inhibiting S100B expression can restore p53-dependent apoptosis in melanoma cells.
  • To elucidate the specific pathways involved in S100B-mediated regulation of p53 activity.

Main Methods:

  • Utilized small interfering RNA (siRNA) to inhibit S100B expression in C8146A melanoma cells.
  • Assessed p53 protein levels, phosphorylation, and downstream gene products (p21, PIDD).
  • Evaluated apoptosis induction through markers like poly(ADP-ribose) polymerase cleavage, caspase activation, and DNA fragmentation.
  • Investigated mitochondrial-independent apoptosis pathways and the role of the Fas death receptor.

Main Results:

  • Inhibition of S100B by siRNA increased p53 protein, phosphorylated p53, and p53 gene products in C8146A cells.
  • siRNA-mediated S100B inhibition restored p53-dependent apoptosis, involving Fas receptor aggregation and caspase activation.
  • Apoptosis induction was independent of mitochondrial pathways.
  • S100B was shown to inhibit UV-induced apoptosis in p53-containing cells, and its reduction reactivated p53-dependent cell death.

Conclusions:

  • Reducing S100B expression activates p53 and its downstream transcriptional activities.
  • The S100B protein contributes to melanoma cell survival by down-regulating p53.
  • Targeting S100B may represent a novel therapeutic strategy for malignant melanoma by reactivating the p53 tumor suppressor pathway.

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