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

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

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Activation of the extracellular-regulated protein kinase 5 (ERK5) has been associated with mitogenic signal transduction. However, conflicting findings have challenged the idea that ERK5 is a critical regulator of cell proliferation. We have addressed this issue by testing the effect of the conditional loss of ERK5 in primary fibroblasts. We have discovered that ERK5 suppressed the expression of the cyclin dependent protein kinase (CDKs) inhibitors, p21 and p27, by decreasing mRNA and protein stability, respectively. As a result, low level CDK2 activity detected in ERK5-deficient cells correlated with a defect in G1 to S phase transition of the cell cycle. Similarly, we found that the malignant MDA-MB-231 human breast cancer cell line was dependent on ERK5 to proliferate. We propose that ERK5 blocks p21 expression in MDA-MB-231 cells via a mechanism that implicates c-Myc-dependent transcriptional regulation of the miR-17-92 cluster. Together with evidence that cancer patients with poor prognosis display a high level of expression of components of the ERK5 signaling pathway, these findings support the hypothesis that ERK5 can be a potential target for cancer therapy. © 2012 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)2360-2368
    Number of pages8
    JournalCellular Signalling
    Volume24
    Issue number12
    DOIs
    Publication statusPublished - Dec 2012

    Keywords

    • CDK
    • Cell cycle
    • ERK5
    • MAPK
    • P21
    • P27

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