The extracellular-regulated protein kinase 5 (ERK5) promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases (CDKs)

Perez-Madrigal, Diana; Finegan, Katherine G.; Paramo, Blanca; Tournier, Cathy

doi:10.1016/j.cellsig.2012.08.001

Cited by 44 publications

(51 citation statements)

References 41 publications

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“…The ERK5 signaling is also integrated into Akt (40) and PKA signaling (35,41,42). In addition, ERK5 suppresses the expression of cyclin-dependent protein kinase inhibitors and regulates cell cycle re-entry (43). Our recent findings that ERK5 regulates rephosphorylation of NFATc4 further expand the repertoire of physiological substrates of ERK5 (44).…”

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confidence: 78%

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Role of Extracellular Signal-regulated Kinase 5 in Adipocyte Signaling

Zhu

Guariglia

et al. 2014

Journal of Biological Chemistry

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Background: Regulation and function of ERK5 in adipose depots is not known. Results: Deletion of ERK5 in adipose depots increases adiposity and adipokine secretion. Reduced phosphorylation and potentiated NFATc4 nuclear localization are found. ERK5 also modulates PKA activation. Conclusion: ERK5 impinges on NFATc4 nucleo-cytoplasmic shuttling and modulates PKA activation in adipocytes. Significance: These results expand the repertoire of ERK5 physiological function and downstream targets.

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confidence: 78%

“…ERK5 suppresses the expression of cyclin-dependent protein kinase inhibitors, such as p21 and p27 (43). The loss of ERK5, therefore, delays cell cycle re-entry and may inadvertently promote cell differentiation.…”

Section: Journal Of Biological Chemistry 6317mentioning

confidence: 99%

Role of Extracellular Signal-regulated Kinase 5 in Adipocyte Signaling

Zhu

Guariglia

et al. 2014

Journal of Biological Chemistry

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“…1A, B). As Erk5 activity has been associated with cell cycle progression, 14,24 we synchronised the cells in G1/S phase by incubating them with thymidine and then stained them with propidium iodide (PI) for cytofluorometric evaluation of the cell cycle. The PI profiles showed that a fraction of shErk5 cells were polyploid (Fig.…”

Section: Thymidine Generates Lethal Dna Damage In Erk5-depleted Jurkamentioning

confidence: 99%

“…11 Erk5 is necessary for proliferation of breast carcinoma cells, 12,13 where it contributes to G1/S transition by inhibiting the p21 and p27 cdk inhibitors. 14 The tumourigenicity of Erk5 has been related to its capacity to interact with promyelocytic leukemia protein and inhibit its tumor suppressor activity. 15 By blocking the interaction of promyelocytic leukemia protein and MDM2 Erk5 allows the inhibition of tumor suppressor p53 by MDM2.…”

Section: Introductionmentioning

confidence: 99%

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

et al. 2015

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An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.

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“…38 On the other hand, treatment with XMD8-92 increased the expression of p27, a cell cycle inhibitor recently reported to be regulated by ERK5. 39,40 Moreover, we found that ERK5 inhibition determined an increase in the expression of p15, another negative regulator of the transition from G0/G1 to S phase, 41 not previously connected to the ERK5 pathway. A possible mechanism linking ERK5 inhibition with increased expression of p27 and p15 is represented by the observed reduction of AKT phosphorylation, and the resulting increased expression of nuclear FoxO4.…”

Section: Discussionmentioning

confidence: 60%

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

Rovida¹,

Maira²,

Cannito³

et al. 2014

European Journal of Cancer

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Objective The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo.Design ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts. ResultsIn tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 silencing prevented cell migration induced by epidermal growth factor or hypoxia and caused cytoskeletal remodelling. In mouse xenografts, the rate of tumour appearance and the size of tumours were significantly lower when Huh-7 was silenced for ERK5. Moreover, systemic treatment with XMD8-92 of mice with established HCC xenografts markedly reduced tumour growth and decreased the expression of the proto-oncogene c-Rel.Conclusions ERK5 regulates the biology of HCC cells and modulates tumour development and growth in vivo. This pathway should be investigated as a possible therapeutic target in HCC. Significance of this study

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The extracellular-regulated protein kinase 5 (ERK5) promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases (CDKs)

Cited by 44 publications

References 41 publications

Role of Extracellular Signal-regulated Kinase 5 in Adipocyte Signaling

Role of Extracellular Signal-regulated Kinase 5 in Adipocyte Signaling

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

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