An ERK5–KLF2 signalling module regulates early embryonic gene expression and telomere rejuvenation in stem cells

Brown, H.; Williams, Charles A. C.; Zhou, Houjiang; Rios-Szwed, Diana; Fernandez-Alonso, Rosalia; Mansoor, Saria; McMulkin, Liam; Toth, Rachel; Gourlay, Robert; Peltier, Julien; Diéguez-Martínez, Nora; Trost, Matthias; Lizcano, José M.; Stavridis, Marios P.; Findlay, Greg M.

doi:10.1042/bcj20210646

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…Strikingly, recent studies have revealed a novel function of ERK5 in the process of stem cells rejuvenation. In particular, ERK5 is able to induce the transcription of the rejuvenation factor Zinc finger and SCAN domain containing 4 (ZSCAN4) at the early embryonic 2-cell stage (2C), consequently increasing telomere length and prolonging the viability of the cell culture [ 123 ]. In addition, ERK5 activity has been found strictly associated with the self-renewal of stem cells.…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

Monti

Celli

Missale

et al. 2022

Cancers

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Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways.

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Section: Introductionmentioning

confidence: 99%

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

Monti

Celli

Missale

et al. 2022

Cancers

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“…Although we found that ERK5 inhibition significantly reduced NEMO/IKK mRNA levels, we cannot discard a role of ERK5 in regulating NEMO/IKK stability, as described for other ERK5 substrates such as KLF2 [41]. Further work will be necessary to establish if ERK5 phosphorylates NEMO/IKK and the implications in the stability of this protein.…”

Section: Mechanistically Erk5 Inhibition Of Ec Cells Resulted In Impa...mentioning

confidence: 64%

“…In this work, we report that ERK5 inhibition or silencing results in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and apoptosis, which was rescued when NEMO/IKKγ was transiently overexpressed. Although we found that ERK5 inhibition significantly reduced NEMO/IKKγ mRNA levels, we cannot discard a role of ERK5 in regulating NEMO/IKKγ stability, as described for other ERK5 substrates such as KLF2 [41]. Further work will be necessary to establish if ERK5 phosphorylates NEMO/IKKγ, and the implications in the stability of this protein.…”

Section: Discussionmentioning

confidence: 68%

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Diéguez-Martínez

Espinosa-Gil

Yoldi

et al. 2022

Preprint

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Endometrial cancer (EC) is the most common type of gynaecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel molecular therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different forms of stress, including oxidative stress and cytokines. Previous evidence support a role for the MEK5-ERK5 pathway in the pathology of several cancers. We have investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition decreased EGF-induced EC cell proliferation, and that depletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic or genetic silencing of ERK5 impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 depletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.

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“…In this work, we report that ERK5 inhibition or silencing results in downregulation of NEMO/IKKγ expression, leading to impaired p65/ RELA activity and apoptosis, which was rescued when NEMO/IKKγ was transiently overexpressed. Although we found that ERK5 inhibition or silencing significantly reduced NEMO/IKKγ mRNA levels, we cannot discard a role of ERK5 in regulating NEMO/IKKγ stability, as described for other ERK5 substrates such as KLF2 [48]. Further work will be necessary to establish if ERK5 phosphorylates NEMO/IKKγ, and the implications on the stability of this protein.…”

Section: Discussionmentioning

confidence: 68%

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Diéguez-Martínez

Espinosa-Gil

Yoldi

et al. 2022

Cell. Mol. Life Sci.

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Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.

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An ERK5–KLF2 signalling module regulates early embryonic gene expression and telomere rejuvenation in stem cells

Cited by 7 publications

References 34 publications

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

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