Renal Damage in Obstructive Nephropathy Is Decreased in Skp2-Deficient Mice

Suzuki, Shingo; Fukasawa, Hirotaka; Kitagawa, Kyoko; Uchida, Chiharu; Hattori, Takayuki; Isobe, Tomoyasu; Oda, Toshiaki; Misaki, Taro; Ohashi, Naro; Nakayama, Keiko; Nakayama, Keiichi I.; Hishida, Akira; Yamamoto, Tatsuo; Kitagawa, Masatoshi

doi:10.2353/ajpath.2007.070279

Cited by 24 publications

(49 citation statements)

References 30 publications

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“…Our findings are consistent with previous research showing that Skp2-deficient mice exhibit cellular accumulation of p27 (11,37). Another finding in our study strongly supported the concept that Skp2-overexpressed MCF-7 cell clones displayed resistance to EGCG, suppressing intracellular p27 accumulation (Fig.…”

Section: Discussionsupporting

confidence: 95%

EGCG Stabilizes p27kip1 in E2-Stimulated MCF-7 Cells through Down-Regulation of the Skp2 Protein

et al. 2008

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Loss of p27Kip1 is associated with a poor prognosis in breast cancer. According to previous findings, a decrease in p27Kip1 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S-phase kinase protein 2 (Skp2). Epigallocatechin-3-gallate (EGCG), the main constituent of green tea, was found to stabilize p27Kip1 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression remains unclear. Here we investigated the mechanisms involved in EGCG's growth inhibition of estrogen-responsive human breast cancer MCF-7 cells. In our results, EGCG increased p27Kip1 and decreased Skp2 in a time- and dose-dependent manner, suggesting that p27Kip1 and Skp2 may be involved in the growth inhibition by EGCG in estrogen-stimulated MCF-7 cells. Interestingly, mRNA levels of p27Kip1 and Skp2 did not significantly change in estrogen-stimulated MCF-7 cells after EGCG treatments. Moreover, overexpression of Skp2 in MCF-7 cells prevented accumulation of p27Kip1 and promoted resistance to the antiproliferative effects of EGCG. This suggests that the down-regulation of the F-box protein Skp2 is the mechanism underlying p27Kip1 accumulation. Furthermore, both tamoxifen and paclitaxel significantly and synergistically enhanced the growth inhibition of MCF-7 cells by EGCG through the down-regulation of Skp2 protein. However, the down-regulation of Skp2 was not always correlate with the up-regulation of p27, suggesting that EGCG-dependent Skp2 down-regulation can influence cell growth in several ways. The therapeutic strategies designed to reduce Skp2 may therefore play an important clinical role in treatment of breast cancer cells.

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Section: Discussionsupporting

confidence: 95%

EGCG Stabilizes p27kip1 in E2-Stimulated MCF-7 Cells through Down-Regulation of the Skp2 Protein

et al. 2008

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“…Kip1 up-regulation in epithelial cells (68). However, in the cornea, desmin is not expressed after simple incision injuries that normally heal without induction of fibrosis (69).…”

Section: Discussionmentioning

confidence: 99%

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin

Bargagna‐Mohan

Paranthan

Hamza

et al. 2012

Journal of Biological Chemistry

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Background: Withaferin A (WFA) is a vimentin-targeting inhibitor that has potent anti-proliferative activity. Results: WFA protects against corneal fibrosis by down-regulating injury-induced vimentin to exert epithelial cell cycle arrest and inhibit myofibroblast expression, which is a mechanism closely mimicked in vimentin-deficient mice during injury healing. Conclusion: Vimentin is a novel fibrosis target. Significance: Ocular fibrotic conditions that overexpress vimentin could be treatable with WFA.

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“…Skp2-mediated p27 kip1 degradation also plays an essential role in growth and adaptive expansion of pancreatic β cells [20]. In kidney, Suzuki et al [21] reported that proliferation of tubular cells, which is a characteristic feature in obstructed kidneys, was significantly decreased in Skp2 –/– mice with obstructive nephropathy, with much greater p27 kip1 accumulation than in Skp2 +/+ mice. However, the above mechanism was studied only in the MC culture model.…”

Section: Discussionmentioning

confidence: 99%

A Novel Target of Mizoribine Inhibiting Mesangial Cell Proliferation: S Phase Kinase-Associated Protein 2

Liu

Xie

et al. 2010

Am J Nephrol

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Background/Aims: Mizoribine (MZR) can inhibit mesangial cell (MC) proliferation, but the mechanism remains unknown. In this study, we investigated the inhibitory effect of MZR on MC proliferation via a cell cycle regulatory protein-dependent mechanism. Methods: We investigated the effect of MZR on MC proliferation and expression of cell cycle regulatory proteins such as cyclin D1, cyclin-dependent kinase 2 and p27^kip1 in primary cultured rat MCs. We further focused on analyzing the effects of MZR on S phase kinase-associated protein 2 (Skp2), which played a crucial role in p27^kip1 degradation. Results: MZR effectively inhibited MC proliferation in primary cultured rat MCs, reduced the expression of cyclin D1 and cyclin-dependent kinase 2, while it dramatically increased the protein level of p27^kip1, maintained the nucleus location of p27^kip1 and induced G1/S arrest. In contrast to the protein level, MZR produced no changes in p27^kip1 mRNA abundance. MZR impaired p27^kip1 degradation through downregulating the expression of Skp2 and this effect was not dependent on its inhibition on DNA synthesis. Skp2 overexpression abolished MZR-induced p27^kip1 accumulation. Conclusion: These results suggested that MZR-induced p27^kip1 accumulation was at least partly mediated by Skp2, and that Skp2 might be a novel target of MZR inhibiting MC proliferation.

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Renal Damage in Obstructive Nephropathy Is Decreased in Skp2-Deficient Mice

Cited by 24 publications

References 30 publications

EGCG Stabilizes p27kip1 in E2-Stimulated MCF-7 Cells through Down-Regulation of the Skp2 Protein

EGCG Stabilizes p27kip1 in E2-Stimulated MCF-7 Cells through Down-Regulation of the Skp2 Protein

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin

A Novel Target of Mizoribine Inhibiting Mesangial Cell Proliferation: S Phase Kinase-Associated Protein 2

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