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, NRAS(Q61R)-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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Mannava S,Omilian AR,Wawrzyniak JA,Fink EE,Zhuang D,Miecznikowski JC,Marshall JR,Soengas MS,Sears RC,Morrison CD,Nikiforov MAdoi
10.1038/onc.2011.339subject
Has Abstractpub_date
2012-03-22 00:00:00pages
1484-92issue
12eissn
0950-9232issn
1476-5594pii
onc2011339journal_volume
31pub_type
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