The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury

Ophascharoensuk, Vuddhidej; Fero, Matthew L.; Hughes, Jeremy; Roberts, James M.; Shankland, Stuart J.

doi:10.1038/nm0598-575

Cited by 168 publications

(132 citation statements)

References 25 publications

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“…p27 Ϫ/Ϫ mice exhibit multiple organ hyperplasia caused by generalized hypercellularity, which is most prominent between 4 to 8 weeks of age (Fero et al, 1996;Kiyokawa et al, 1996;Nakayama et al, 1996). p27 Ϫ/Ϫ mice also have an increased incidence of tumors, consistent with the body of evidence attributing a protective role to p27 in the progression and prognosis of proliferative diseases such as cancer (Catzavelos et al, 1997;Cordon-Cardo et al, 1998;Loda et al, 1997;Ophascharoensuk et al, 1998). These observations led to the hypothesis that the lack of p27 would enhance intimal proliferation after injury.…”

Section: Discussionmentioning

confidence: 56%

Effect of p27 Deficiency and Rapamycin on Intimal Hyperplasia: In Vivo and In Vitro Studies Using a p27 Knockout Mouse Model

Roqué

Reis

Cordon‐Cardo

et al. 2001

Laboratory Investigation

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SUMMARY:Rapamycin, an immunosuppressant and antiproliferative agent, reduces intimal hyperplasia after arterial injury in animal models and in a preliminary study in humans. Rapamycin treatment reportedly increases expression of p27, a cyclin-dependent kinase inhibitor. This mechanism was tested using a p27-deficient (p27 Ϫ/Ϫ) murine model. Aortic smooth muscle cells from wild-type (WT) and p27 Ϫ/Ϫ mice were isolated and cultured. Cell proliferation, assessed by cell count and 3 H-thymidine incorporation, was inhibited significantly by rapamycin in WT and p27 Ϫ/Ϫ cells at concentrations of 1 ng/ml, 10 ng/ml, and 100 ng/ml (p Ͻ 0.05, versus control). The in vivo effect on intimal hyperplasia was studied in p27 Ϫ/Ϫ and WT mice after femoral artery transluminal injury. Rapamycin treatment was started 2 days before injury and maintained for 2 weeks (1 mg/kg per 48 hours, ip). No significant differences in intima-to-media ratio were found between WT (1.1 Ϯ 0.1) and p27 Ϫ/Ϫ mice (1.0 Ϯ 0.1) 4 weeks after injury. Rapamycin significantly (p Ͻ 0.05) reduced intima-to-media ratios in both WT (0.7 Ϯ 0.1) and p27 Ϫ/Ϫ mice (0.5 Ϯ 0.1), compared with untreated mice. p27 deficiency did not alter the arterial wall proliferative response to injury. The inhibitory effect of rapamycin on intimal hyperplasia occurred via a p27-independent mechanism. The in vitro data showed that this effect was mediated through decreased proliferation and enhanced apoptosis. (Lab Invest 2001, 81:895-903).E xcessive vascular smooth muscle cell (SMC) proliferation is a feature of restenosis after percutaneous coronary interventions and is present in spontaneous atherosclerotic lesions (Casscells, 1992;Foegh and Virmani, 1993;Ross, 1999). Control of cell proliferation by targeting cell-cycle regulation has been proposed as a therapeutic strategy to prevent development of intimal hyperplasia (Braun-Dullaeus et al, 1998;Chang et al, 1995;Chen et al, 1997;Li and Brooks, 1999;MacLellan and Majesky, 1997;Mann et al, 1999;Morishita et al, 1994.Cyclin-dependent kinase inhibitors (CDKIs) are critical regulators of cell-cycle progression. These proteins bind to complexes formed by cyclins and cyclindependent kinases (CDKs), inhibiting their enzymatic activity and thereby inducing cell-cycle arrest (Sherr and Roberts, 1995). p27 kip1 is an ubiquitous CDKI with a predominant role in regulating G1/S phase transition, determining cell entry into S phase or withdrawal from the cycle (Koff et al, 1993;Polyak et al, 1994).Mitogenic stimuli, such as platelet-derived growth factor (PDGF) and interleukin-2, down-regulate p27 (Nourse et al, 1994). Low intracellular levels of free p27 enable retinoblastoma protein (pRB) hyperphosphorylation by cyclin-CDK complexes, subsequent release of E2F transcription factor, and cell replication .Rapamycin is a potent growth inhibitor that impairs progression through G1/S transition (Marx et al, 1995). Proposed mechanisms of action include inhibition of p70S6 kinase, impairment of pRB hyperphosphorylation, and prevention of p27 down-r...

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Section: Discussionmentioning

confidence: 56%

Effect of p27 Deficiency and Rapamycin on Intimal Hyperplasia: In Vivo and In Vitro Studies Using a p27 Knockout Mouse Model

Roqué

Reis

Cordon‐Cardo

et al. 2001

Laboratory Investigation

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“…Cells with increased CDK2 activity are more vulnerable to UV induced apoptosis and reducing CDK2 activity decreases apoptosis Previous studies have shown that apoptosis is increased in proliferating cell populations in certain forms of apoptosis (Danno and Horio, 1982;Nishioka and Welsh, 1994;Syljuasen and McBride, 1999) (Baker et al, 1994;Ophascharoensuk et al, 1998). However, the mechanisms linking these processes are not fully elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…The association of speci®c cyclin-CDKs and apoptosis has also been shown in vivo. Mice transgenic for both cyclin A and CDK2 show a greater incidence of apoptosis (Bortner and Rosenberg, 1995), and increased cyclin A-CDK2 activity coincides with a marked increase in apoptosis in in¯ammatory injury (Ophascharoensuk et al, 1998). Taken together, these studies demonstrate that speci®c cyclin-CDK complexes are involved in both the proliferative and apoptotic pathways following injury.…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2002

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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.

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“…p27 has been shown to safeguard against excessive cell proliferation in experimental glomerulonephritis and ureteral obstruction (38). While p27 has beneficial effects in these specific pathophysiologic settings, it appears to play a detrimental role in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

The Lack of Cyclin Kinase Inhibitor p27Kip1 Ameliorates Progression of Diabetic Nephropathy

Awazu¹,

Omori²,

Ishikura³

et al. 2003

Journal of the American Society of Nephrology

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The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury

Cited by 168 publications

References 25 publications

Effect of p27 Deficiency and Rapamycin on Intimal Hyperplasia: In Vivo and In Vitro Studies Using a p27 Knockout Mouse Model

Effect of p27 Deficiency and Rapamycin on Intimal Hyperplasia: In Vivo and In Vitro Studies Using a p27 Knockout Mouse Model

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

The Lack of Cyclin Kinase Inhibitor p27Kip1 Ameliorates Progression of Diabetic Nephropathy

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