Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells
Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells
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DOI：
10.1242/dmm.001016
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发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Mione, Marina
中科院分区：
文献类型：
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作者：
Santoriello, Cristina;Deflorian, Gianluca;Mione, Marina
具有组成性活性的“致癌”H-RAS可以驱动人类癌症的增殖和转化，或者是细胞衰老的有效诱导剂。此外，由于种系突变引起的Ras途径的异常激活可导致严重的发育障碍。在这项研究中，我们已经产生了组成型表达低水平，或可以诱导表达高水平，致癌H-RAS的转基因斑马鱼。我们观察到，在其种系中携带整合转基因的鱼显示出Costello综合征的几个特征，Costello综合征是一种由基因H-RAS中的激活突变引起的罕见遗传疾病，并且可以用作该疾病的模型。在Costello样鱼中，低水平的致癌H-RAS表达与大脑和心脏中成体祖细胞区室中增殖减少和衰老标记物增加以及激活的DNA损伤反应相关。H-RAS通过热休克诱导型启动子在幼虫中过表达导致过度增殖，激活DNA损伤反应和tp 53依赖的细胞周期停滞。因此，癌基因诱导的成体增殖细胞的衰老有助于Costello综合征的发展，并提供了一个替代途径的转化存在广泛的组成型活性H-RAS表达。
Constitutively active, 'oncogenic' H-RAS can drive proliferation and transformation in human cancer, or be a potent inducer of cellular senescence. Moreover, aberrant activation of the Ras pathway owing to germline mutations can cause severe developmental disorders. In this study we have generated transgenic zebrafish that constitutively express low levels, or can be induced to express high levels, of oncogenic H-RAS. We observed that fish carrying the integrated transgene in their germline display several hallmarks of Costello syndrome, a rare genetic disease caused by activating mutations in the gene H-RAS, and can be used as a model for the disease. In Costello-like fish, low levels of oncogenic H-RAS expression are associated with both reduced proliferation and an increase in senescence markers in adult progenitor cell compartments in the brain and heart, together with activated DNA damage responses. Overexpression of H-RAS through a heat-shock-inducible promoter in larvae led to hyperproliferation, activation of the DNA damage response and tp53-dependent cell cycle arrest. Thus, oncogene-induced senescence of adult proliferating cells contributes to the development of Costello syndrome and provides an alternative pathway to transformation in the presence of widespread constitutively active H-RAS expression.