Ligand activation of peroxisome proliferator-activated receptor-beta/delta inhibits cell proliferation in human HaCaT keratinocytes.
Ligand activation of peroxisome proliferator-activated receptor-beta/delta inhibits cell proliferation in human HaCaT keratinocytes.
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DOI：
10.1124/mol.108.050609
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发表时间：
2008-11
影响因子：
3.6
通讯作者：
Peters JM
中科院分区：
文献类型：
--
作者：
Borland MG;Foreman JE;Girroir EE;Zolfaghari R;Sharma AK;Amin S;Gonzalez FJ;Ross AC;Peters JM
尽管有强有力的证据表明过氧化物酶体增殖物激活受体 (PPAR)-β/δ 的配体激活会诱导终末分化并减弱细胞生长，但一些研究表明 PPARβ/δ 实际上会增强细胞增殖。例如，最近有人提出，视黄酸 (RA) 是 PPARβ/δ 的配体，并通过激活 PPARβ/δ 来增强细胞增殖。本研究使用两种高度特异性的 PPARβ/δ 配体 [4-[[[2-[3-氟-4-(三氟甲基)苯基]-4-甲基-5-噻唑基]甲基]硫基]-2-甲基苯氧基乙酸 (GW0742) 和2-甲基-4-((4-甲基-2-(4-三氟甲基苯基)-1,3-噻唑-5-基)-甲硫基)苯氧基-乙酸(GW501516)]和RA。 PPARβ/δ 配体和 RA 均抑制 HaCaT 角质形成细胞的细胞增殖。 GW0742 和 GW501516 增加了已知 PPARβ/δ 靶基因的表达，而 RA 则没有； RA 增加了已知视黄酸受体/类视黄醇 X 受体靶基因的表达，而 GW0742 不影响这些基因。 GW0742、GW501516 和 RA 不会调节 3-磷酸肌醇依赖性蛋白激酶的表达或改变蛋白激酶 B 磷酸化。通过流式细胞术定量测定，GW0742 和 RA 增加了膜联蛋白 V 染色。还在野生型和 PPARβ/δ 缺失的原代小鼠角质形成细胞中检查了 GW0742 和 RA 的作用，以确定 PPARβ/δ 在调节细胞生长中的具体作用。尽管 GW0742 对角质形成细胞增殖的抑制是 PPARβ/δ 依赖性的，但 RA 对细胞增殖的抑制作用在两种基因型中均存在。这些研究结果表明，PPARβ/δ 的配体激活通过 PPARβ/δ 依赖性机制抑制角质形成细胞增殖。相反，观察到的 RA 对小鼠和人类角质细胞增殖的抑制是由 PPARβ/δ 独立机制介导的，与 RA 通过激活 PPARβ/δ 增强细胞增殖的观点不一致。
Although there is strong evidence that ligand activation of peroxisome proliferator-activated receptor (PPAR)-β/δ induces terminal differentiation and attenuates cell growth, some studies suggest that PPARβ/δ actually enhances cell proliferation. For example, it was suggested recently that retinoic acid (RA) is a ligand for PPARβ/δ and potentiates cell proliferation by activating PPARβ/δ. The present study examined the effect of ligand activation of PPARβ/δ on cell proliferation, cell cycle kinetics, and target gene expression in human HaCaT keratinocytes using two highly specific PPARβ/δ ligands [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy acetic acid (GW0742) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516)] and RA. Both PPARβ/δ ligands and RA inhibited cell proliferation of HaCaT keratinocytes. GW0742 and GW501516 increased expression of known PPARβ/δ target genes, whereas RA did not; RA increased the expression of known retinoic acid receptor/retinoid X receptor target genes, whereas GW0742 did not affect these genes. GW0742, GW501516, and RA did not modulate the expression of 3-phosphoinositide-dependent protein kinase or alter protein kinase B phosphorylation. GW0742 and RA increased annexin V staining as quantitatively determined by flow cytometry. The effects of GW0742 and RA were also examined in wild-type and PPARβ/δ-null primary mouse keratinocytes to determine the specific role of PPARβ/δ in modulating cell growth. Although inhibition of keratinocyte proliferation by GW0742 was PPARβ/δ-dependent, inhibition of cell proliferation by RA occurred in both genotypes. Results from these studies demonstrate that ligand activation of PPARβ/δ inhibits keratinocyte proliferation through PPARβ/δ-dependent mechanisms. In contrast, the observed inhibition of cell proliferation in mouse and human keratinocytes by RA is mediated by PPARβ/δ-independent mechanisms and is inconsistent with the notion that RA potentiates cell proliferation by activating PPARβ/δ.
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影响因子：
9.7
作者：
Kanekura, T;Higashi, Y;Kanzaki, T
通讯作者：
Kanzaki, T
影响因子：
4.8
作者：
Kim, DJ;Murray, IA;Peters, JM
通讯作者：
Peters, JM
影响因子：
3.6
作者：
Demerjian, M;Man, MQ;Feingold, KR
通讯作者：
Feingold, KR
影响因子：
4.8
作者：
Kim, DJ;Akiyama, TE;Peters, JM
通讯作者：
Peters, JM
影响因子：
9.7
作者：
CHEN, LC;KIRCHHOFF, S;DE LUCA, LM
通讯作者：
DE LUCA, LM