The extracellular-regulated protein kinase 5 (ERK5) promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases (CDKs).
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.
University of Manchester, Faculty of Life Sciences, Manchester, UK.
Diana
D
Perez-Madrigal
Katherine G
KG
Finegan
Blanca
B
Paramo
Cathy
C
Tournier
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016196:S Phase; D014158:Transcription, Genetic
D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D048054:Mitogen-Activated Protein Kinase 7