| First Author | Lambrecht C | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 4 | Pages | 544-552 |
| PubMed ID | 28967903 | Mgi Jnum | J:257885 |
| Mgi Id | MGI:6120173 | Doi | 10.1038/onc.2017.350 |
| Citation | Lambrecht C, et al. (2018) Loss of protein phosphatase 2A regulatory subunit B56delta promotes spontaneous tumorigenesis in vivo. Oncogene 37(4):544-552 |
| abstractText | 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 B56delta 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-3beta Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56delta-null livers. Thus, uncontrolled c-Myc activity due to B56delta-driven GSK-3beta 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. |
