Mouse Rad1 deletion enhances susceptibility for skin tumor development.
Mouse Rad1 deletion enhances susceptibility for skin tumor development.
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DOI：
10.1186/1476-4598-9-67
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发表时间：
2010-03-24
期刊：
影响因子：
37.3
通讯作者：
Hang H
中科院分区：
文献类型：
--
作者：
Han L;Hu Z;Liu Y;Wang X;Hopkins KM;Lieberman HB;Hang H
细胞不断暴露于来自细胞代谢物以及环境遗传毒素的压力。由这些基因毒素引起的DNA损伤可以通过DNA修复与细胞周期检查点合作来有效地修复。未修复的DNA损伤可导致细胞死亡、基因突变和癌症。Rad 1蛋白，从酵母到人类进化上保守，作为单体以及9-1-1蛋白复合物中的组分存在于细胞中。Rad 1在DNA修复和细胞周期检查点控制中起着至关重要的作用，但其在致癌作用中的作用尚不清楚。为了解决这个问题，我们构建了Mrad 1缺失的小鼠。杂合子Mrad 1突变小鼠之间的交配产生Mrad 1 +/+和Mrad 1 +/-，但没有Mrad 1-/-后代，表明Mrad 1无效是胚胎致死的。Mrad 1 +/-小鼠在1岁半时未表现出明显的异常。使用DMBA-TPA组合处理在小鼠皮肤上诱导肿瘤。与Mrad 1 +/+动物相比，Mrad 1 +/-小鼠皮肤上的肿瘤更大，数量更多，出现更早。从Mrad 1 +/-小鼠分离的角质形成细胞具有比Mrad 1 +/+对照细胞显著更多的自发DNA双链断裂，增殖较慢，并且具有轻微增强的自发凋亡。这些数据表明，Mrad 1可能通过维持基因组完整性，对预防肿瘤发展很重要。Mrad 1杂合性缺失对角质形成细胞增殖和凋亡的影响不同于Mrad 9杂合性缺失（来自我们先前的研究），这表明Mrad 1除了在小鼠细胞中的Mrad 9-Mrad 1-Mhus 1复合物中起作用之外，还独立于Mrad 9发挥功能。
Cells are constantly exposed to stresses from cellular metabolites as well as environmental genotoxins. DNA damage caused by these genotoxins can be efficiently fixed by DNA repair in cooperation with cell cycle checkpoints. Unrepaired DNA lesions can lead to cell death, gene mutation and cancer. The Rad1 protein, evolutionarily conserved from yeast to humans, exists in cells as monomer as well as a component in the 9-1-1 protein complex. Rad1 plays crucial roles in DNA repair and cell cycle checkpoint control, but its contribution to carcinogenesis is unknown. To address this question, we constructed mice with a deletion of Mrad1. Matings between heterozygous Mrad1 mutant mice produced Mrad1+/+ and Mrad1+/- but no Mrad1-/- progeny, suggesting the Mrad1 null is embryonic lethal. Mrad1+/- mice demonstrated no overt abnormalities up to one and half years of age. DMBA-TPA combinational treatment was used to induce tumors on mouse skin. Tumors were larger, more numerous, and appeared earlier on the skin of Mrad1+/- mice compared to Mrad1+/+ animals. Keratinocytes isolated from Mrad1+/- mice had significantly more spontaneous DNA double strand breaks, proliferated slower and had slightly enhanced spontaneous apoptosis than Mrad1+/+ control cells. These data suggest that Mrad1 is important for preventing tumor development, probably through maintaining genomic integrity. The effects of heterozygous deletion of Mrad1 on proliferation and apoptosis of keratinocytes is different from those resulted from Mrad9 heterozygous deletion (from our previous study), suggesting that Mrad1 also functions independent of Mrad9 besides its role in the Mrad9-Mrad1-Mhus1 complex in mouse cells.
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影响因子：
11.2
作者：
Hu Z;Liu Y;Zhang C;Zhao Y;He W;Han L;Yang L;Hopkins KM;Yang X;Lieberman HB;Hang H
通讯作者：
Hang H
影响因子：
4.8
作者：
Burtelow, MA;Roos-Mattjus, PMK;Karnitz, LM
通讯作者：
Karnitz, LM
影响因子：
10.5
作者：
ENOCH, T;CARR, AM;NURSE, P
通讯作者：
NURSE, P
DOI：
10.1007/bf00266239
发表时间：
1992-04-01
期刊：
MOLECULAR & GENERAL GENETICS
影响因子：
--
作者：
LIEBERMAN, HB;HOPKINS, KM;CHU, HM
通讯作者：
CHU, HM
影响因子：
14.9
作者：
MURRAY, JM;CARR, AM;WATTS, FZ
通讯作者：
WATTS, FZ