Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse
Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse
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DOI：
10.1038/sj.onc.1202417
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发表时间：
1999-02-11
期刊：
影响因子：
8
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
--
作者：
Balasubramanian, S;Kim, KH;Mukhtar, H
端粒酶是一种将六核苷酸重复序列TTAGGG添加到染色体末端的核糖核蛋白酶，端粒酶的激活在细胞永生化和癌变过程中起着至关重要的作用。端粒酶与细胞周期进程密切相关，受细胞周期蛋白、细胞周期蛋白依赖性激酶(CDKs)和细胞周期蛋白依赖性激酶抑制因子(CDKs)的调控，这些调控分子的异常表达可引起细胞周期的改变，导致细胞生长失控，这是肿瘤的普遍特征，皮肤癌是人类最常见的癌症形式，太阳紫外线辐射是其主要原因。在此，我们研究了在UVB诱导的SKH-1无毛小鼠肿瘤形成过程中端粒酶活性和细胞周期调节分子蛋白表达的调节。每隔4周处死动物，在表皮中进行研究，未照射的小鼠的表皮中几乎检测不到端粒酶活性。UVB暴露后，端粒酶活性从暴露后第4周开始逐渐升高。随着暴露剂量的增加，端粒酶活性的增强持续或进一步增强，在乳头状瘤和癌症中，端粒酶活性相似，是对照小鼠表皮的45倍。Western印迹分析显示，在UVB照射过程中，乳头状瘤和癌组织中细胞周期蛋白D1和细胞周期蛋白E及其调节亚基CDK4和CDK2的蛋白表达上调。CDK6、CKIS、p16/Ink4a、p21/Waf1和p27/Kip1蛋白表达在WE暴露皮肤中无明显变化，但在乳头状瘤和癌组织中均有显著上调。这些结果表明，端粒酶的激活可能参与了UVB诱导的小鼠皮肤肿瘤的发生，端粒酶活性的增加可能与细胞周期的G1期有关。
Telomerase is a ribonucleoprotein enzyme that adds hexanucleotide repeats TTAGGG to the ends of chromosomes, Telomerase activation is known to play a crucial role in cell-immortalization and carcinogenesis. Telomerase is shown to have a correlation with cell cycle progression, which is controlled by the regulation of cyclins, cyclin dependent kinases (cdks) and cyclin dependent kinase inhibitors (cdkis), Abnormal expression of these regulatory molecules may cause alterations in cell cycle with uncontrolled cell growth, a universal feature of neoplasia, Skin cancer is the most prevalent form of cancer in humans and the solar UV radiation is its major cause. Here, we investigated modulation in telomerase activity and protein expression of cell cycle regulatory molecules during the development of UVB-induced tumors in SKH-1 hairless mice, The mice were exposed to 180 mjoules/cm(2) UVB radiation, thrice weekly for 24 weeks. The animals were sacrificed at 4 week intervals and the studies were performed in epidermis, Telomerase activity was barely detectable in the epidermis of non-irradiated mouse. UVB exposure resulted in a progressive increase in telomerase activity starting from the 4th week of exposure. The increased telomerase activity either persisted or further increased with the increased exposure, In papillomas and carcinomas the enzyme activity was comparable and was 45-fold higher than in the epidermis of control mice. Western blot analysis showed an upregulation in the protein expression of cyclin D1 and cyclin E and their regulatory subunits cdk4 and cdk2 during the course of UVB exposure and in papillomas and carcinomas. The protein expression of cdk6 and ckis viz, p16/Ink4A, p21/Waf1 and p27/Kip1 did not show any significant change in WE exposed skin, but significant upregulation was observed both in papillomas and carcinomas. The results suggest that telomerase activation may be involved in UVB-induced tumorigenesis in mouse skin and that increased telomerase activity may be associated with G1 phase of the cell cycle.