PPARgamma ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells.
PPARgamma ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells.
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DOI：
10.1111/j.1582-4934.2009.00966.x
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发表时间：
2010-06
影响因子：
5.3
通讯作者：
Barrera G
中科院分区：
文献类型：
--
作者：
Toaldo C;Pizzimenti S;Cerbone A;Pettazzoni P;Menegatti E;Daniela B;Minelli R;Giglioni B;Dianzani MU;Ferretti C;Barrera G
在人类细胞中，端粒的长度取决于端粒酶的活性。这种活性和人端粒酶逆转录酶（hTERT）的催化亚基的表达在大多数人类癌症中强烈上调。hTERT的表达受不同的转录因子调控，如c-Myc、Mad 1和Sp1。在这项研究中，我们证明了15 d-PG J2和罗格列酮（分别是一种内源性和合成的过氧化物酶体增殖物激活受体γ（PPARγ）配体）抑制CaCo-2结肠癌细胞中hTERT表达和端粒酶活性。此外，这两种配体抑制c-Myc蛋白的表达和其E-box DNA结合活性。此外，Mad 1蛋白表达和其E-box DNA结合活性强烈增加15 d-PG J2，并在较小程度上，罗格列酮。Sp1转录因子的表达及其GC盒DNA结合活性不受两种PPARγ配体的影响。通过用pmaxFP-绿色-PRL质粒构建体瞬时转染CaCo-2细胞获得的结果表明，15 d-PG J2和效力较小的罗格列酮强烈降低hTERT核心启动子活性，所述pmaxFP-绿色-PRL质粒构建体含有功能性hTERT核心启动子（包括一个E-box和五个GC-box）及其E-box缺失序列，所述E-box缺失序列克隆在绿色荧光蛋白报告基因的上游。Myc/Mad/Max结合的E盒显示出比Sp1的GC盒更高的活性。通过使用GW 9662（一种PPARγ拮抗剂），我们证明了15 d-PG J2的作用是完全不依赖于PPARγ的，而罗格列酮对hTERT表达的作用似乎是部分不依赖于PPARγ的。15 d-PG J2和罗格列酮通过调节Myc/Max/Mad 1网络调节hTERT表达，可能代表了这些物质抑制细胞增殖的新作用机制。
In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of human telomerase reverse transcriptase (hTERT) is strongly up-regulated in most human cancers. hTERT expression is regulated by different transcription factors, such as c-Myc, Mad1 and Sp1. In this study, we demonstrated that 15d-PG J2 and rosiglitazone (an endogenous and synthetic peroxisome proliferators activated receptor γ (PPARγ) ligand, respectively) inhibited hTERT expression and telomerase activity in CaCo-2 colon cancer cells. Moreover, both ligands inhibited c-Myc protein expression and its E-box DNA binding activity. Additionally, Mad1 protein expression and its E-box DNA binding activity were strongly increased by 15d-PG J2 and, to a lesser extent, by rosiglitazone. Sp1 transcription factor expression and its GC-box DNA binding activity were not affected by both PPARγ ligands. Results obtained by transient transfection of CaCo-2 cells with pmaxFP-Green-PRL plasmid constructs containing the functional hTERT core promoter (including one E-box and five GC-boxes) and its E-box deleted sequences, cloned upstream of the green fluorescent protein reporter gene, demonstrated that 15d-PG J2, and with minor effectiveness, rosiglitazone, strongly reduced hTERT core promoter activity. E-boxes for Myc/Mad/Max binding showed a higher activity than GC-boxes for Sp1. By using GW9662, an antagonist of PPARγ, we demonstrated that the effects of 15d-PG J2 are completely PPARγ independent, whereas the effects of rosiglitazone on hTERT expression seem to be partially PPARγ independent. The regulation of hTERT expression by 15d-PG J2 and rosiglitazone, through the modulation of the Myc/Max/Mad1 network, may represent a new mechanism of action of these substances in inhibiting cell proliferation.
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影响因子：
3.6
作者：
Berry, EBE;Keelan, JA;Mitchell, MD
通讯作者：
Mitchell, MD
影响因子：
4.1
作者：
Allred, CD;Kilgore, MW
通讯作者：
Kilgore, MW
影响因子：
2.9
作者：
Barrera G;Toaldo C;Pizzimenti S;Cerbone A;Pettazzoni P;Dianzani MU;Ferretti C
通讯作者：
Ferretti C
影响因子：
64.5
作者：
KLIEWER, SA;LENHARD, JM;LEHMANN, JM
通讯作者：
LEHMANN, JM
影响因子：
64.8
作者：
GREIDER, CW;BLACKBURN, EH
通讯作者：
BLACKBURN, EH