p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase

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 tumo...

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Autores principales:	Lepakshe S.V. Madduri, Nichole D. Brandquist, Chitra Palanivel, Geoffrey A. Talmon, Michael J. Baine, Sumin Zhou, Charles A. Enke, Keith R. Johnson, Michel M. Ouellette, Ying Yan
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	p53 FBXL20 PR55α PP2A c-Myc Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/8cdb3c1f0b98459aa43240965cbaf58f
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spelling	oai:doaj.org-article:8cdb3c1f0b98459aa43240965cbaf58f2021-11-30T04:14:35Zp53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase1476-558610.1016/j.neo.2021.10.002https://doaj.org/article/8cdb3c1f0b98459aa43240965cbaf58f2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621000877https://doaj.org/toc/1476-5586We 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.Lepakshe S.V. MadduriNichole D. BrandquistChitra PalanivelGeoffrey A. TalmonMichael J. BaineSumin ZhouCharles A. EnkeKeith R. JohnsonMichel M. OuelletteYing YanElsevierarticlep53FBXL20PR55αPP2Ac-MycNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 23, Iss 12, Pp 1192-1203 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	p53 FBXL20 PR55α PP2A c-Myc Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	p53 FBXL20 PR55α PP2A c-Myc Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lepakshe S.V. Madduri Nichole D. Brandquist Chitra Palanivel Geoffrey A. Talmon Michael J. Baine Sumin Zhou Charles A. Enke Keith R. Johnson Michel M. Ouellette Ying Yan p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
description	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.
format	article
author	Lepakshe S.V. Madduri Nichole D. Brandquist Chitra Palanivel Geoffrey A. Talmon Michael J. Baine Sumin Zhou Charles A. Enke Keith R. Johnson Michel M. Ouellette Ying Yan
author_facet	Lepakshe S.V. Madduri Nichole D. Brandquist Chitra Palanivel Geoffrey A. Talmon Michael J. Baine Sumin Zhou Charles A. Enke Keith R. Johnson Michel M. Ouellette Ying Yan
author_sort	Lepakshe S.V. Madduri
title	p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
title_short	p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
title_full	p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
title_fullStr	p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
title_full_unstemmed	p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase
title_sort	p53/fbxl20 axis negatively regulates the protein stability of pr55α, a regulatory subunit of pp2a ser/thr phosphatase
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8cdb3c1f0b98459aa43240965cbaf58f
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p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase

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