Ciglitazone-induced cellular anti-proliferation increases p27 kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation

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Abstract

While it is well established that PPARγ ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARγ ligands is unclear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.

Original languageEnglish (US)
Pages (from-to)809-816
Number of pages8
JournalCellular Signalling
Volume17
Issue number7
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

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Cyclin-Dependent Kinase Inhibitor p27
Proteasome Endopeptidase Complex
Cell Proliferation
Peroxisome Proliferator-Activated Receptors
Ligands
Colonic Neoplasms
G1 Phase Cell Cycle Checkpoints
Inhibition (Psychology)
ciglitazone
Proteolysis
Genes
Cell Cycle
Apoptosis
Messenger RNA
Growth

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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title = "Ciglitazone-induced cellular anti-proliferation increases p27 kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation",
abstract = "While it is well established that PPARγ ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARγ ligands is unclear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.",
author = "Fei Chen and Lawrence Harrison",
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N2 - While it is well established that PPARγ ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARγ ligands is unclear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.

AB - While it is well established that PPARγ ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARγ ligands is unclear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.

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