p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase.
p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase.
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DOI：
10.1016/j.neo.2021.10.002
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Yan Y
中科院分区：
文献类型：
--
作者：
Madduri LSV;Brandquist ND;Palanivel C;Talmon GA;Baine MJ;Zhou S;Enke CA;Johnson KR;Ouellette MM;Yan Y
我们之前报道了PP2A丝氨酸/苏氨酸磷酸酶的调控亚基PR55α在支持肿瘤发生和胰腺癌恶性表型所需的关键致癌途径中的重要作用。本报告的研究揭示了p53肿瘤抑制因子通过FBXL20抑制PR55α蛋白稳定性的新机制，FBXL20是p53的靶基因，作为SCF (Skp1_Cullin1_F-box) E3泛素连接酶复合物的底物识别组分，促进其靶蛋白的蛋白酶体降解。我们的研究表明，通过sirna敲低、基因缺失、hpv - e6介导的降解或表达功能缺失突变体p53R175H使p53失活，可导致PR55α蛋白稳定性增加，同时伴有FBXL20蛋白表达降低和PR55α泛素化降低。随后的研究表明，siRNA敲低FBXL20可以模拟p53缺失，减少PR55α泛素化，增加PR55α蛋白的稳定性。功能测试表明，异位p53R175H或PR55α表达导致c-Myc蛋白稳定性增加，同时c-Myc- t58去磷酸化，这是一种PR55α底物，其磷酸化促进c-Myc降解。在表达p53R175H或在更大程度上过表达PR55α的正常人胰腺细胞中，也观察到锚定非依赖性增殖的显著增加。与胰腺癌中常见的p53功能缺失一致，FBXL20 mRNA在胰腺癌组织中的表达明显低于胰腺正常组织，低FBXL20水平与患者生存率低相关。总的来说，这些研究描绘了p53/FBXL20轴负调控PR55α蛋白稳定性的新机制。
We have previously reported an important role of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, in the support of critical oncogenic pathways required for oncogenesis and the malignant phenotype of pancreatic cancer. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor inhibits the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins. Our studies show that inactivation of p53 by siRNA-knockdown, gene-deletion, HPV-E6-mediated degradation, or expression of the loss-of-function mutant p53R175H results in increased PR55α protein stability, which is accompanied by reduced protein expression of FBXL20 and decreased ubiquitination of PR55α. Subsequent studies demonstrate that knockdown of FBXL20 by siRNA mimics p53 deficiency, reducing PR55α ubiquitination and increasing PR55α protein stability. Functional tests indicate that ectopic p53R175H or PR55α expression results in an increase of c-Myc protein stability with concomitant dephosphorylation of c-Myc-T58, which is a PR55α substrate, whose phosphorylation otherwise promotes c-Myc degradation. A significant increase in anchorage-independent proliferation is also observed in normal human pancreatic cells expressing p53R175H or, to a greater extent, overexpressing PR55α. Consistent with the common loss of p53 function in pancreatic cancer, FBXL20 mRNA expression is significantly lower in pancreatic cancer tissues compared to pancreatic normal tissues and low FBXL20 levels correlate with poor patient survival. Collectively, these studies delineate a novel mechanism by which the p53/FBXL20 axis negatively regulates PR55α protein stability.
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影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
6.2
作者：
Hein, Ashley L.;Brandquist, Nichole D.;Yan, Ying
通讯作者：
Yan, Ying
影响因子：
11.5
作者：
Klauschen, Frederick;Wienert, Stephan;von Minckwitz, Gunter
通讯作者：
von Minckwitz, Gunter
影响因子：
5.6
作者：
Gnoni A;Licchetta A;Scarpa A;Azzariti A;Brunetti AE;Simone G;Nardulli P;Santini D;Aieta M;Delcuratolo S;Silvestris N
通讯作者：
Silvestris N
影响因子：
5.4
作者：
FOSTER, SA;DEMERS, GW;GALLOWAY, DA
通讯作者：
GALLOWAY, DA