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ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.

ABSTRACT: Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5-KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.

SUBMITTER: Arconada-Luque E

PROVIDER: S-EPMC9316148 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.

Arconada-Luque Elena E Jiménez-Suarez Jaime J Pascual-Serra Raquel R Nam-Cha Syong Hyun SH Moline Teresa T Cimas Francisco J FJ Fliquete Germán G Ortega-Muelas Marta M Roche Olga O Fernández-Aroca Diego M DM Muñoz Velasco Raúl R García-Flores Natalia N Garnés-García Cristina C Sánchez-Fdez Adrián A Matilla-Almazán Sofía S Sánchez-Arévalo Lobo Víctor J VJ Hernández-Losa Javier J Belandia Borja B Pandiella Atanasio A Esparís-Ogando Azucena A Ramón Y Cajal Santiago S Del Peso Luis L Sánchez-Prieto Ricardo R Ruiz-Hidalgo María José MJ

Cancers 20220719 14

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived fro ...[more]

PMID: 35884568

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Project description:Diabetes mellitus (DM) contributes to the exacerbation of left ventricle (LV) dysfunction after myocardial infarction (MI). Activation of ERK5, an atypical mitogen activated protein kinase with transcriptional activity, inhibits apoptosis and LV dysfunction after doxorubicin treatment. SUMOylation has been proposed as a negative regulator of various transcription factors. In the current study, we investigated the role of ERK5-SUMOylation in ERK5 transcriptional activity as well as on DM-mediated exacerbation of LV dysfunction and apoptosis after MI. ERK5 wild-type transcriptional activity was inhibited by Ubc9 (SUMO E2 conjugase) or PIAS1 (E3 ligase), but not in the ERK5-SUMOylation-site defective mutant (K6R/K22R). H2O2 and high glucose, 2 well-known mediators of diabetes, induced ERK5-SUMOylation, and the K6R/K22R mutant, dominant negative form of Ubc9, and siRNA-PIAS1 reversed H2O2-mediated reduction of ERK5 transcriptional activity in cardiomyocytes, indicating the presence of SUMOylation-dependent ERK5 transcriptional repression. Constitutively active form of MEK5alpha (CA-MEK5alpha) inhibited ERK5-SUMOylation independent of kinase activity, but dependent on MEK5-ERK5 association. To investigate the pathological role of ERK5-SUMOylation in DM mice after MI, we used cardiac specific CA-MEK5alpha transgenic mice (CA-MEK5alpha-Tg). MI was induced in streptozotocin (STZ)-injected (DM+MI group) or vehicle-injected mice (MI group) by ligating the left coronary artery. The ERK5-SUMOylation was increased in the DM+MI, but not in the MI group. ERK5-SUMOylation, the exacerbation of LV dysfunction, and the number of TUNEL-positive cells in DM+MI was significantly inhibited in CA-MEK5alpha-Tg mice. Of note, we could not detect any difference of cardiac function after MI in non-diabetic CA-MEK5alpha-Tg and non-transgenic littermate control mice. These results demonstrated that ERK5 transcriptional activity is subject to downregulation by diabetes-dependent SUMOylation, which resulted in a proapoptotic condition contributing to poor post-MI LV function.

Dataset Information

ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.

Publications

ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.

Similar Datasets

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