Wang X, Tournier CRegulation of cellular functions by the ERK5 signalling pathway. Cell Signal 18: 753-760

Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
Cellular Signalling (Impact Factor: 4.32). 07/2006; 18(6):753-60. DOI: 10.1016/j.cellsig.2005.11.003
Source: PubMed

ABSTRACT Extracellular-regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase (MAPK) regulated by a wide range of mitogens and cellular stresses. Since its cloning in 1995, the lack of biological tools, including antibodies and specific inhibitors, have made it one of the least studied MAPK subfamilies. The discovery that ERK5 was an important contributor to cell survival mechanisms has increased interest in this signalling pathway. The ability of inhibitors of the classical MAPK (ERK1/2) cascade to block ERK5 activation suggested that ERK5 might regulate some cellular functions originally attributed to ERK1/2. For example, ERK5 is suspected to mediate the effects of numerous oncogenes. A link between abnormal levels of ERK5 expression and cancers was established by the analysis of human tumours. Recently, the targeted deletions of the erk5 and the mek5 genes in mice have provided genetic evidence that the ERK5 cascade is a non-redundant signalling pathway essential for normal cardiovascular development. The analysis of genetically modified mice in which the erk5 gene can be specifically deleted in certain tissues is shedding light into the physiological function of the ERK5 pathway during development and pathogenesis.

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    • "Overexpression of miR-143 induced with anti-miR-Bcl-2 partially reversed the inhibition of cell proliferation and promoted apoptosis in the HeLa cells expressing miR-143 [43]. Another experimentally verified target of tumor suppressor microRNAs miR-143 and miR-145 is the cellular gene ERK5 (also known as MAPK7) a mitogenactivated protein kinase (MAPK) regulated by a wide range of mitogens and by cell stress, which promotes cell growth and proliferation in response to tyrosine kinase signaling [44]. In the bladder cancer cell line T24, prostate cancer cell lines LNCaP and C4-2, and the Burkitt lymphoma cell line Raji, ERK5 expression levels were found to be reduced and cell proliferation was inhibited in response to increased levels of miR-143 and miR-145 [40, 45–47]. "
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    ABSTRACT: MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3 í® í°-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer.
    BioMed Research International 03/2015; 2015. DOI:10.1155/2015/374924 · 2.71 Impact Factor
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    • "To the best of our knowledge, this is the first evidence where non-degradative ubiquitination (predominantly K63-linked ubiquitin) is involved in the physical and functional disassembly of a " classical " MAPK module, thus adding another layer in the inactivation of MAPKs. ERK5 is a relatively less studied MAPK despite its importance in vertebrate development and in pathogenic conditions such as cardiac hypertrophy and cancer (Wang & Tournier, 2006). The MEKK2/3-MEK5-ERK5 cascade is activated by numerous stimuli and assembled by distinct PB1 domain-mediated protein–protein interactions, though a role for scaffold proteins such as Lad has been suggested (Sun et al, 2001; Drew et al, 2012). "
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    ABSTRACT: Mitogen-activated protein kinases (MAPKs) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-regulated kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or cIAP1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5-dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the physical and functional disassembly of ERK5-MAPK module and human muscle cell differentiation.
    The EMBO Journal 06/2014; 33(16). DOI:10.15252/embj.201487808 · 10.43 Impact Factor
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    • "We have confirmed this in leukemic cells with down regulated expression of ERK5 (Charni et al., 2010). ERK5 mediates survival and proliferation (Wang and Tournier, 2006), notably in transformed cells of hematopoietic origin (Buschbeck et al., 2005; Carvajal-Vergara et al., 2005; Garaude et al., 2005, 2006). However, the mechanism by which ERK5 regulates cell metabolism is still unknown. "
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    ABSTRACT: Cancer cell metabolism differs from that of non-transformed cells in the same tissue. This specific metabolism gives tumor cells growing advantages besides the effect in increasing anabolism. One of these advantages is immune evasion mediated by a lower expression of the mayor histocompatibility complex class I molecules. The extracellular-signal-regulated kinase-5 regulates both mayor histocompatibility complex class I expression and metabolic activity. However, the mechanisms underlying are largely unknown. We show here that extracellular-signal-regulated kinase-5 regulates the transcription of the NADH(+)-dependent histone deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin 1) in leukemic Jurkat T cells. This involves the activation of the transcription factor myocyte enhancer factor-2 and its binding to the sirt1 promoter. In addition, extracellular-signal-regulated kinase-5 is required for T cell receptor-induced and oxidative stress-induced full Sirtuin 1 expression. Extracellular-signal-regulated kinase-5 induces the expression of promoters containing the antioxidant response elements through a Sirtuin 1-dependent pathway. On the other hand, down modulation of extracellular-signal-regulated kinase-5 expression impairs the anti-oxidant response. Notably, the extracellular-signal-regulated kinase-5 inhibitor BIX02189 induces apoptosis in acute myeloid leukemia tumor cells without affecting T cells from healthy donors. Our results unveil a new pathway that modulates metabolism in tumor cells. This pathway represents a promising therapeutic target in cancers with deep metabolic layouts such as acute myeloid leukemia.
    The International Journal of Biochemistry & Cell Biology 05/2014; 53. DOI:10.1016/j.biocel.2014.05.026 · 4.05 Impact Factor
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