The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation

Abstract

Apoptosis is closely linked to proliferation. In this study we showed that inducing apoptosis in mouse mesangial cells with ultraviolet (UV) irradiation was associated with increased cyclin A-cyclin dependent kinase (CDK) 2 activity. Inhibiting CDK2 activity with Roscovitine or dominant negative mutant reduced apoptosis. Because apoptosis typically begins in the cytoplasm, we tested the hypothesis that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell. Our results showed that cyclin A-CDK2 was nuclear in proliferating cells. However, inducing apoptosis in proliferating cells with UV irradiation was associated with a decrease in nuclear cyclin A and CDK2 protein levels. This coincided with an increase in protein and kinase activity for cyclin A-CDK2 in the cytoplasm. Translocation of cyclin A-CDK2 also occurred in p537/7 mesangial cells. Finally, we showed that caspase-3 activity was signi®-cantly reduced by inhibiting CDK2 activity with Roscovitine. In summary, our results show that apoptosis is associated with an increase in cytoplasmic cyclin A-CDK2 activity, which is p53 independent and upstream of caspase-3. We propose that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell.

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

“…Recently, it has been shown that the nucleocytoplasmic translocation of Cdk2 is under the control of p42/p44 MAPKs in fibroblasts (43,44). Cytoplasmic mislocalization of Cdk2 has also been reported to be a key event in vitamin D-mediated growth inhibition of prostate cancer cells (45) and in irradiation-induced apoptosis in mouse mesangial cells (46). In this study, we show that the subcellular localization of Cdk2 provides a novel mechanism whereby p38 MAPKs could regulate cell cycle progression.…”

Cdk2 acts upstream of mitochondrial permeability transition during paclitaxel-induced apoptosis

“…The rapid upregulation of Cdk2 activity is functionally associated with the onset of apoptosis in several experimental systems, including growth factor-deprived human endothelial cells, irradiated lymphocytes, heat shocked cells, and dexamethasone-treated cells (Levkau et al, 1998;Hiromura et al, 2002;Choi et al, 2007). Thus, Cdk2, a key regulator of the cell cycle, has been suggested to play a role in apoptosis.…”

“…Cdk1/cyclin B1 activity shields human cells against extrinsic death stimuli (Matthess et al, 2010). Cdk2 activation is mainly detected in apoptotic cells that exhibit G 1 /S phase arrest, as observed in ultraviolet irradiation-treated mesangial cells (Hiromura et al, 2002), etoposide-induced human leukemic cells (Choi et al, 2007;Bastin-Coyette et al, 2011), growth factor-deprived HUVEC cells (Levkau et al, 1998), G-Rh2-induced human hepatoma cells (Jin et al, 2000), panaxadiol-induced SK-HEP-1 cells (Jin et al, 2003). In previous reports, we showed that Cdk2 but not Cdc2 is selectively up-regulated and this upregulation is required for the induction of apoptosis in several cancer cell lines, including SK-HEP-1 cells and HeLa cells induced by treatment with ginsenoside-Rh2 (G-Rh2) (Jin et al, 2000) or panaxadiol (Jin et al, 2003).…”

Expression of a novel stress-inducible protein, sestrin 2, in rat glomerular parietal epithelial cells

“…Apoptosis was measured by Hoechst 33342 (Dojindo Molecular Technologies, Tokyo, Japan) staining and by careful morphological analysis, as previously reported (13). Apoptotic cells were counted in six randomly selected fields and expressed as a percentage in triplicate.…”