Publication
Title
Loss of protein phosphatase 2A regulatory subunit B56 promotes spontaneous tumorigenesis in vivo
Author
Abstract
Protein Phosphatase 2A (PP2A) enzymes counteract diverse kinase-driven oncogenic pathways and their function is frequently impaired in cancer. PP2A inhibition is indispensable for full transformation of human cells, but whether loss of PP2A is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe spontaneous tumor development in knockout mice for Ppp2r5d, encoding the PP2A regulatory B56 delta subunit. Several primary tumors were observed, most commonly, hematologic malignancies and hepatocellular carcinomas (HCCs). Targeted immunoblot and immunohistochemistry analysis of the HCCs revealed heterogeneous activation of diverse oncogenic pathways known to be suppressed by PP2A-B56. RNA sequencing analysis unveiled, however, a common role for oncogenic c-Myc activation in the HCCs, independently underscored by c-Myc Ser62 hyperphosphorylation. Upstream of c-Myc, GSK-3 beta Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56 delta-null livers. Thus, uncontrolled c-Myc activity due to B56 delta-driven GSK-3 beta inactivation is the likely tumor predisposing factor. Our data provide the first compelling mouse genetics evidence sustaining the tumor suppressive activity of a single PP2A holoenzyme, constituting the final missing incentive for full clinical development of PP2A as cancer biomarker and therapy target.
Language
English
Source (journal)
Oncogene. - London
Publication
London : 2018
ISSN
0950-9232
DOI
10.1038/ONC.2017.350
Volume/pages
37 :4 (2018) , p. 544-552
ISI
000423331600012
Pubmed ID
28967903
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 06.03.2018
Last edited 09.10.2023
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