MEF-2 isoforms' (A-D) roles in development and tumorigenesis

Madugula, Kiran; Mulherkar, Ria; Khan, Zafar K.; Chigbu, De Gaulle I.; Patel, Dip; Harhaj, Edward W.

doi:10.18632/oncotarget.26763

Cited by 15 publications

(13 citation statements)

References 280 publications

(291 reference statements)

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“…Interestingly, in these processes, ERK5 has a determinant role 61‐63 . Furthermore, downstream targets of ERK5 signalling pathway, as MEF2 transcription factors, which have a critical role related to the oncogenic capacities of ERK5, could be implicated in our observations (for a review see 64 ). In fact, MEF2 transcription factors have been related to cell migration and invasion, 65 angiogenesis 66 or EMT transition 67 .…”

Section: Discussionmentioning

confidence: 78%

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

Ortega-Muelas

Roche

Fernández-Aroca

et al. 2021

J Cellular Molecular Medi

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Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5‐dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.

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Section: Discussionmentioning

confidence: 78%

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

Ortega-Muelas

Roche

Fernández-Aroca

et al. 2021

J Cellular Molecular Medi

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“…Besides, through alternative splicing at the mRNA level [85], and post-translational modifications such as phosphorylation or dephosphorylation [11], acetylation [3], sumoylation [63] and S-nitrosylation [52], MEF2C appears various expression pattern and transactivation functions. In addition, MEF2C mediates physiological processes such as cardiac morphogenesis, angiogenesis, muscle cell differentiation, bone development, and neural or lymphatic system development [44].…”

Section: Introductionmentioning

confidence: 99%

Progress on the roles of MEF2C in neuropsychiatric diseases

Zhang

Zhao

2022

Mol Brain

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Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.

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“…MEF-2 is a member of the MCM-Agamous-Deficiens-Serum response factor (MADS) box group of transcription factors. The MEF-2 family consists of four isoforms (A-D, reviewed in (18)), which are well studied in the development of skeletal, cardiac, and neural tissues with established roles in embryogenesis. Interestingly, some of these isoforms play critical roles in T-cell development by regulating the transcription of the T-cell growth factor interleukin-2 (IL-2) (19).…”

Section: Introductionmentioning

confidence: 99%

Over-representation of MEF-2 isoforms (A/C) is associated with HTLV-1-induced acute ATLL and their recruitment to 3’LTR facilitates HBZ expression from the antisense promoter via interactions with Menin and Jun D

Madugula

Joseph

Teixeira

et al. 2021

Preprint

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Background. HTLV-1 is a complex human retrovirus and an etiologic agent causing a malignant and intractable T-cell neoplasia termed Adult T-cell leukemia and lymphoma (ATLL). Patients suffering from ATLL present with poor prognoses and a dearth of treatment options warranting a continuous need to develop novel therapeutic targets. In contrast to the HTLV-1 transactivator protein Tax, HTLV-1 bZIP protein (HBZ) maintains its expression in ATLL cells. The HBZ gene is encoded from the antisense strand of the provirus and is not under the transcriptional control of the 5’ long terminal repeat (LTR) unlike other viral genes such as Tax. Few modifications have been reported in the 3’LTR, which regulates HBZ expression. Herein, we delineate the activities of a transcription factor MEF (Myocyte enhancer factor)-2 at both 5’ and 3’LTRs in the context of ATLL progression and maintenance. Results. In this study, we report that two MEF isoforms (2A and 2C) are highly overexpressed in acute ATLL patients from North America. These isoforms are recruited to the viral promoters at both the 5’ and 3’LTRs. Their knockdown by shRNAs resulted in the downregulation of Tax and HBZ expression as well as a significant decrease in proliferation and cell cycle arrest in ATLL cells. Similarly, chemical inhibition of MEF proteins by MC1568 (a selective Class IIa HDAC inhibitor) resulted in the cytotoxicity of ATLL cells in vitro as well as reduction of proviral load and viral gene expression in vivo. At the molecular level, high enrichment of MEF-2C occurred at the 3’LTR along with cofactors Menin, Jun D, and Sp1/Sp3 thus providing a novel mechanism of regulation at the antisense promoter of HTLV-1. Conclusions. This study establishes MEF-2 as critical players in ATLL, which interacts with Tax and HBZ at their respective promoters highlighting a novel mechanism of regulation at the 3’LTR involving Jun D and Menin. MEF signaling represent a potential target for therapeutic intervention.

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MEF-2 isoforms' (A-D) roles in development and tumorigenesis

Cited by 15 publications

References 280 publications

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

Progress on the roles of MEF2C in neuropsychiatric diseases

Over-representation of MEF-2 isoforms (A/C) is associated with HTLV-1-induced acute ATLL and their recruitment to 3’LTR facilitates HBZ expression from the antisense promoter via interactions with Menin and Jun D

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