RGD Reference Report - The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis. - Rat Genome Database

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The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis.

Authors: Bokemeyer, D  Panek, D  Kitahara, M  Trzaskos, JM  Muller, CE  Hockemeyer, J  Kunter, U  Boor, P  Floege, J  Kramer, HJ  Ostendorf, T 
Citation: Bokemeyer D, etal., Nephrol Dial Transplant. 2007 Dec;22(12):3431-41. Epub 2007 Sep 24.
RGD ID: 2293563
Pubmed: PMID:17893107   (View Abstract at PubMed)
DOI: DOI:10.1093/ndt/gfm428   (Journal Full-text)

BACKGROUND: In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown. METHODS: To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase. RESULTS: In stimulated MC, inhibition of ERK reduced cyclin-dependent kinase 2 (CDK2) phosphorylation, CDK2 activity and cyclin E/A expression, whereas downregulation of CDK inhibitor p27(Kip1) expression was inhibited. In vivo, U0126 was given to rats in the acute phase of anti-Thy 1.1 GN. We previously showed that glomerular cell proliferation was reduced by 67% upon treatment with the inhibitor compared to nephritic controls. Now, we detected a significant increase in renal CDK2-activity/phosphorylation in the nephritic controls, that was significantly and dose-dependently reduced by ERK inhibition. CDK2 activation was accompanied by an increase in renal expression of cyclins E/A and the enhanced binding of these cyclins to CDK2 in the nephritic controls. These changes were blunted by U0126 treatment. Finally, we noted an increased expression and CDK2-binding of p27(KIP1) protein in the nephritic controls which was decreased in U0126 treated rats. CONCLUSIONS: Our observations provide the first evidence that ERK is an intracellular regulator of renal CDK2 activity in vivo in a glomerulonephritis model.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
membranoproliferative glomerulonephritis  ISOCdk2 (Rattus norvegicus)2293563; 2293563 RGD 
membranoproliferative glomerulonephritis  IMP 2293563 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cdk2  (cyclin dependent kinase 2)

Genes (Mus musculus)
Cdk2  (cyclin dependent kinase 2)

Genes (Homo sapiens)
CDK2  (cyclin dependent kinase 2)


Additional Information