Developmental context determines latency of MYC-induced tumorigenesis.
Developmental context determines latency of MYC-induced tumorigenesis.
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DOI：
10.1371/journal.pbio.0020332
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发表时间：
2004-11
期刊：
影响因子：
9.8
通讯作者：
Felsher DW
中科院分区：
文献类型：
--
作者：
Beer S;Zetterberg A;Ihrie RA;McTaggart RA;Yang Q;Bradon N;Arvanitis C;Attardi LD;Feng S;Ruebner B;Cardiff RD;Felsher DW
肿瘤生物学中的一个谜是，不同类型的癌症在不同年龄组中流行。一种可能的解释是，特定癌基因在特定细胞类型中引起肿瘤发生的能力取决于表观遗传参数，如发育环境。为了解决这一假设，我们使用四环素调控系统来产生转基因小鼠，其中c-MYC人转基因的表达可以在鼠肝细胞中受到条件性调控。MYC诱导肿瘤发生的能力取决于发育背景。在胚胎和新生小鼠中，肝脏中MYC过表达诱导了显著的细胞增殖和肿瘤的立即发生。相比之下，在成年小鼠中，MYC过表达诱导细胞生长和DNA复制而没有有丝分裂细胞分裂，并且小鼠仅在延长的潜伏期后才死于肿瘤形成。在成年肝细胞中，MYC激活未能诱导细胞分裂，这至少部分是通过激活p53介导的。令人惊讶的是，细胞凋亡不是MYC诱导肿瘤发生的障碍。癌基因诱导肿瘤发生的能力通常受到发育特异性机制的抑制。成体体细胞已经进化出防止单个癌基因单独启动细胞生长、DNA复制和有丝分裂细胞分裂的机制，从而防止任何单个遗传事件诱导肿瘤发生。转基因小鼠模型表明，发育背景可能是儿童和成人肿瘤谱不同的原因
One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis. A transgenic mouse model demonstrates that developmental context may be the reason why the spectrum of tumors differs in children and adults
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影响因子：
14.5
作者：
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通讯作者：
El-Deiry, WS
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