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GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration

The epithelium-specific Ets transcription factor, SPDEF, plays a critical role in metastasis of prostate and breast cancer cells. While enhanced SPDEF expression blocks migration and invasion, knockdown of SPDEF expression enhances migration, invasion, and metastasis of cancer cells. SPDEF expressio...

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Autores principales: Tamura, Rodrigo E., Paccez, Juliano D., Duncan, Kristal C., Morale, Mirian G., Simabuco, Fernando M., Dillon, Simon, Correa, Ricardo G., Gu, Xuesong, Libermann, Towia A., Zerbini, Luiz F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924684/
https://www.ncbi.nlm.nih.gov/pubmed/26885618
http://dx.doi.org/10.18632/oncotarget.7355
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author Tamura, Rodrigo E.
Paccez, Juliano D.
Duncan, Kristal C.
Morale, Mirian G.
Simabuco, Fernando M.
Dillon, Simon
Correa, Ricardo G.
Gu, Xuesong
Libermann, Towia A.
Zerbini, Luiz F.
author_facet Tamura, Rodrigo E.
Paccez, Juliano D.
Duncan, Kristal C.
Morale, Mirian G.
Simabuco, Fernando M.
Dillon, Simon
Correa, Ricardo G.
Gu, Xuesong
Libermann, Towia A.
Zerbini, Luiz F.
author_sort Tamura, Rodrigo E.
collection PubMed
description The epithelium-specific Ets transcription factor, SPDEF, plays a critical role in metastasis of prostate and breast cancer cells. While enhanced SPDEF expression blocks migration and invasion, knockdown of SPDEF expression enhances migration, invasion, and metastasis of cancer cells. SPDEF expression and activation is tightly regulated in cancer cells; however, the precise mechanism of SPDEF regulation has not been explored in detail. In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway. As a consequence of CDK11p58 mediated degradation of SPDEF, this loss of SPDEF protein results in increased prostate cancer cell migration and invasion. In contrast, knockdown of CDK11p58 protein expression by interfering RNA or SPDEF overexpression inhibit migration and invasion of cancer cells. We demonstrate that CDK11p58 mediated degradation of SPDEF is attenuated by Growth Arrest and DNA damage-inducible 45 (GADD45) α and, two proteins inducing G2/M cell cycle arrest. We show that GADD45 α and γ, directly interact with CDK11p58 and thereby inhibit CDK11p58 activity, and consequentially SPDEF phosphorylation and degradation, ultimately reducing prostate cancer cell migration and invasion. Our findings provide new mechanistic insights into the complex regulation of SPDEF activity linked to cancer metastasis and characterize a previously unidentified SPDEF/CDK11p58/GADD45α/γ pathway that controls SPDEF protein stability and SPDEF-mediated effects on cancer cell migration and invasion.
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spelling pubmed-49246842016-07-13 GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration Tamura, Rodrigo E. Paccez, Juliano D. Duncan, Kristal C. Morale, Mirian G. Simabuco, Fernando M. Dillon, Simon Correa, Ricardo G. Gu, Xuesong Libermann, Towia A. Zerbini, Luiz F. Oncotarget Research Paper The epithelium-specific Ets transcription factor, SPDEF, plays a critical role in metastasis of prostate and breast cancer cells. While enhanced SPDEF expression blocks migration and invasion, knockdown of SPDEF expression enhances migration, invasion, and metastasis of cancer cells. SPDEF expression and activation is tightly regulated in cancer cells; however, the precise mechanism of SPDEF regulation has not been explored in detail. In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway. As a consequence of CDK11p58 mediated degradation of SPDEF, this loss of SPDEF protein results in increased prostate cancer cell migration and invasion. In contrast, knockdown of CDK11p58 protein expression by interfering RNA or SPDEF overexpression inhibit migration and invasion of cancer cells. We demonstrate that CDK11p58 mediated degradation of SPDEF is attenuated by Growth Arrest and DNA damage-inducible 45 (GADD45) α and, two proteins inducing G2/M cell cycle arrest. We show that GADD45 α and γ, directly interact with CDK11p58 and thereby inhibit CDK11p58 activity, and consequentially SPDEF phosphorylation and degradation, ultimately reducing prostate cancer cell migration and invasion. Our findings provide new mechanistic insights into the complex regulation of SPDEF activity linked to cancer metastasis and characterize a previously unidentified SPDEF/CDK11p58/GADD45α/γ pathway that controls SPDEF protein stability and SPDEF-mediated effects on cancer cell migration and invasion. Impact Journals LLC 2016-02-12 /pmc/articles/PMC4924684/ /pubmed/26885618 http://dx.doi.org/10.18632/oncotarget.7355 Text en Copyright: © 2016 Tamura et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Tamura, Rodrigo E.
Paccez, Juliano D.
Duncan, Kristal C.
Morale, Mirian G.
Simabuco, Fernando M.
Dillon, Simon
Correa, Ricardo G.
Gu, Xuesong
Libermann, Towia A.
Zerbini, Luiz F.
GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title_full GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title_fullStr GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title_full_unstemmed GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title_short GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration
title_sort gadd45α and γ interaction with cdk11p58 regulates spdef protein stability and spdef-mediated effects on cancer cell migration
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924684/
https://www.ncbi.nlm.nih.gov/pubmed/26885618
http://dx.doi.org/10.18632/oncotarget.7355
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