Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells.
Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I-deficient mice, and inhibition of Cdk5 increased in vitro the susceptibility to apoptosis in response to cellular damage. In addition, levels of the prosurvival proteins Bcl-2 and Bcl-XL were reduced in podocytes and neurons from cyclin I-deficient mice, and restoration of Bcl-2 or Bcl-XL expression prevented injury-induced apoptosis. Furthermore, we found that levels of phosphorylated MEK1/2 and ERK1/2 were decreased in cyclin I-deficient podocytes and that inhibition of MEK1/2 restored Bcl2 and Bcl-XL protein levels. Of interest, this pathway was also defective in mice with experimental glomerulonephritis. Taken together, these data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in terminally differentiated cells that functions via MAPK signaling to modulate levels of the prosurvival proteins Bcl-2 and Bcl-XL.
Brinkkoetter
Paul T
PT
Division of Nephrology, University of Washington, Seattle, Washington 98195-6521, USA.
Olivier
Paul
P
Wu
Jimmy S
JS
Henderson
Scott
S
Krofft
Ronald D
RD
Pippin
Jeffrey W
JW
Hockenbery
David
D
Roberts
James M
JM
Shankland
Stuart J
SJ
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D056749:Cyclin I / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D050199:Podocytes / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
C494812:Bcl2l1 protein, mouse; C534757:Ccni protein, mouse; C492236:Cdk5r1 protein, mouse; D056749:Cyclin I; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C505409:Casp3 protein, mouse; D053148:Caspase 3