Constitutive telomerase expression promotes mammary carcinomas in aging mice
Constitutive telomerase expression promotes mammary carcinomas in aging mice
复制标题
DOI：
10.1073/pnas.112515399
复制
发表时间：
2002-06-11
影响因子：
11.1
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Artandi, SE;Alson, S;DePinho, RA
端粒酶在绝大多数人类癌症中上调，并用于阻止进行性端粒缩短，最终阻止可能的癌细胞获得完全恶性表型。与人类相比，实验室小鼠具有长端粒，即使在早期的端粒酶缺陷小鼠中，端粒储备水平也足以避免基于端粒的检查点反应并允许完全恶性进展。小鼠中的这些特征提供了一个机会，以确定强制性高水平端粒酶活性是否可以提供超出其维持端粒长度和功能的能力的功能。在这里，我们报告的生成和表征的转基因小鼠，表达端粒酶催化亚基（mTERT）在各种组织中的高水平。mTERT的表达增强了几种组织中的端粒酶活性，包括乳腺、脾细胞和培养的小鼠胚胎成纤维细胞。在小鼠胚胎成纤维细胞中，mTERT过表达延长了端粒长度，但没有阻止培养诱导的复制停滞，从而加强了这种现象与隐性端粒缩短无关的观点。然而，在相当比例的老年女性中，强大的端粒酶活性与乳腺上皮内瘤变和浸润性乳腺癌的自发发展相关。这些数据表明，即使在端粒储备充足的情况下，增强的mTERT表达也可以促进自发性癌症的发展。
Telomerase is up-regulated in the vast majority of human cancers and serves to halt the progressive telomere shortening that ultimately blocks would-be cancer cells from achieving a full malignant phenotype. In contrast to humans, the laboratory mouse possesses long telomeres and, even in early generation telomerase-deficient mice, the level of telomere reserve is sufficient to avert telomere-based checkpoint responses and to permit full malignant progression. These features in the mouse provide an opportunity to determine whether enforced high-level telomerase activity can serve functions that extend beyond its ability to sustain telomere length and function. Here, we report the generation and characterization of transgenic mice that express the catalytic subunit of telomerase (mTERT) at high levels in a broad variety of tissues. Expression of mTERT conferred increased telomerase enzymatic activity in several tissues, including mammary gland, splenocytes, and cultured mouse embryonic fibroblasts. In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. Robust telomerase activity, however, was associated with the spontaneous development of mammary intra-epithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females. These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve.