Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells
Paul T. Brinkkoetter, Paul Olivier, Jimmy S. Wu, Scott Henderson, Ronald D. Krofft, Jeffrey W. Pippin, David Hockenbery, James M. Roberts, Stuart J. Shankland
Paul T. Brinkkoetter, Paul Olivier, Jimmy S. Wu, Scott Henderson, Ronald D. Krofft, Jeffrey W. Pippin, David Hockenbery, James M. Roberts, Stuart J. Shankland
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Research Article Nephrology

Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells

Abstract

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.

Authors

Paul T. Brinkkoetter, Paul Olivier, Jimmy S. Wu, Scott Henderson, Ronald D. Krofft, Jeffrey W. Pippin, David Hockenbery, James M. Roberts, Stuart J. Shankland

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Figure 7

Decreased ERK1/2 activation and increased caspase-3 cleavage in cyclin I–null mice with experimental glomerulonephritis.

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Decreased ERK1/2 activation and increased caspase-3 cleavage in cyclin I...
Experimental glomerulonephritis was induced in 10- to 12-week-old WT and cyclin I–null mice by administration of anti-glomerular antibody. (A–C) Activation of ERK1/2 was assessed by immunostaining for p-ERK1/2 Thr202/Tyr204. There was a significant decrease in glomerular pERK1/2 staining at day 7 of nephritis in cyclin I–null mice (P < 0.05, ANOVA). (D–F) Apoptosis was quantified by immunostaining for caspase-3 cleavage adjacent to Asp175. Both WT and cyclin I–null mice showed increased caspase-3 cleavage in podocytes following disease induction. However, there was significantly more caspase-3 cleavage in cyclin I–null mice at day 7 compared with WT mice (P < 0.01, ANOVA). Depicted are representative glomeruli. Data shown represent mean + SD.