MEK1 and MEK2, different regulators of the G1/S transition.
The ERK cascade is activated by hormones, cytokines, and growth factors that result in either proliferation or growth arrest depending on the duration and intensity of the ERK activation. Here we provide evidence that the MEK1/ERK module preferentially provides proliferative signals, whereas the MEK2/ERK module induces growth arrest at the G1/S boundary. Depletion of either MEK subtype by RNA interference generated a unique phenotype. The MEK1 knock down led to p21cip1 induction and to the appearance of cells with a senescence-like phenotype. Permanent ablation of MEK1 resulted in reduced colony formation potential, indicating the importance of MEK1 for long term proliferation and survival. MEK2 deficiency, in contrast, was accompanied by a massive induction of cyclin D expression and, thus, CDK4/6 activation followed by nucleophosmin hyperphosphorylation and centrosome over-amplification. Our results suggest that the two MEK subtypes have distinct ways to contribute to a regulated ERK activity and cell cycle progression.
Boehringer Ingelheim Austria GmbH, Dr. Boehringer Gasse 5-11, A-1121 Vienna.
Siegfried
S
Ussar
Tilman
T
Voss
D001483:Base Sequence; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D056741:Cyclin D; D051357:Cyclin-Dependent Kinase 2; D016213:Cyclins / Q000235:genetics; D017931:DNA Primers; D004789:Enzyme Activation; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000172:deficiency / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D056741:Cyclin D; D016213:Cyclins; D017931:DNA Primers; D034741:RNA, Small Interfering; C482128:MAP2K2 protein, human; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human