Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells
Paul T. Brinkkoetter, … , James M. Roberts, Stuart J. Shankland
Paul T. Brinkkoetter, … , James M. Roberts, Stuart J. Shankland
Published September 1, 2009
Citation Information: J Clin Invest. 2009;119(10):3089-3101. https://doi.org/10.1172/JCI37978.
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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 10

Cyclin I regulates specific Bcl-2 family proteins in vivo.

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Cyclin I regulates specific Bcl-2 family proteins in vivo. (A) Glomeruli...
(A) Glomeruli were isolated and pooled from the kidneys of 6 animals from each strain, divided into 2 samples, and loaded separately on the gel. Compared with WT glomeruli (lanes 1, 2), levels of Bcl-2 and Bcl-XL were reduced in cyclin null glomeruli (lanes 3, 4). Nephrin, a protein expressed selectively and constitutively in podocytes, was included as a loading control in addition to β-actin and GAPDH to rule out any potential loading differences in protein from podocytes. (B) Compared with brain protein lysates harvested from cyclin I WT mice (lane 1) under physiological, nonstressed conditions, the protein levels of Bcl-2 and Bcl-XL were decreased in cyclin I–null mice (lane 2). Bax levels remain unchanged; β-actin was used as loading control. Taken together, these data show that similar to the cultured cells, the absence of cyclin I also regulates Bcl-2 and Bcl-XL in postmitotic organs in vivo.