PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells

S. Mannava, A. R. Omilian, J. A. Wawrzyniak, E. E. Fink, D. Zhuang, J. C. Miecznikowski, J. R. Marshall, M. S. Soengas, R. C. Sears, C. D. Morrison, M. A. Nikiforov

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Oncoprotein C-MYC is overexpressed in human metastatic melanomas and melanoma-derived cells where it is required for the suppression of oncogene-induced senescence (OIS). The genetic events that maintain high levels of C-MYC in melanoma cells and their role in OIS are unknown. Here we report that C-MYC in cells from several randomly chosen melanoma lines was upregulated at the protein level, and largely because of the increased protein stability. Of all known regulators of C-MYC stability, levels of B56α subunit of the PP2A tumor suppressor complex were substantially suppressed in all human melanoma cells compared with normal melanocytes. Accordingly, immunohistochemical analysis revealed that the lowest and the highest amounts of PP2A-B56α were predominantly detected in metastatic melanoma tissues and in primary melanomas from patients with good clinical outcome, respectively. Importantly, PP2A-B56α overexpression suppressed C-MYC in melanoma cells and induced OIS, whereas depletion of PP2A-B56α in normal human melanocytes upregulated C-MYC protein levels and suppressed BRAF V600E-and, less efficiently, NRASQ61R-induced senescence. Our data reveal a mechanism of C-MYC overexpression in melanoma cells and identify a functional role for PP2A-B56α in OIS of melanocytic cells.

Original languageEnglish (US)
Pages (from-to)1484-1492
Number of pages9
JournalOncogene
Volume31
Issue number12
DOIs
StatePublished - Mar 22 2012

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Keywords

  • C-MYC
  • PP2A
  • melanoma
  • senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Mannava, S., Omilian, A. R., Wawrzyniak, J. A., Fink, E. E., Zhuang, D., Miecznikowski, J. C., Marshall, J. R., Soengas, M. S., Sears, R. C., Morrison, C. D., & Nikiforov, M. A. (2012). PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene, 31(12), 1484-1492. https://doi.org/10.1038/onc.2011.339