Increased tumorigenicity and sensitivity to ionizing radiation upon loss of chromosomal protein HMGN1
Increased tumorigenicity and sensitivity to ionizing radiation upon loss of chromosomal protein HMGN1
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DOI：
10.1158/0008-5472.can-05-0310
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Bustin, M
中科院分区：
文献类型：
--
作者：
Birger, Y;Catez, F;Bustin, M
我们报告了HMGN 1（一种改变染色质纤维致密化的核小体结合蛋白）的缺失增加了细胞对电离辐射的敏感性和小鼠的肿瘤负荷。电离辐射处理的Hmgn 1（-/-）小鼠的死亡率和肿瘤负荷高于其Hmgn 1（+/+）同窝小鼠。Hmgn 1（-/-）成纤维细胞具有改变的G（2）-M检查点激活，并且对电离辐射过敏。Hmgn 1（-/-）成纤维细胞的电离辐射超敏性和异常的G（2）-M检查点激活可以通过表达野生型HMGN 1的质粒进行转染而逆转，但不能通过表达不与染色质结合的突变型HMGN蛋白的质粒进行转染。转化的Hmgn 1（-/-）成纤维细胞在软琼脂中生长，并在裸鼠中产生肿瘤，其效率显著高于Hmgn 1（+/+）成纤维细胞，这表明Hmgn 1蛋白的缺失破坏了控制增殖和生长的细胞事件。Hingn 1（-/-）小鼠比Hmgn 1（+/+）同窝小鼠具有更高的多种恶性肿瘤和转移的发生率。我们认为，HMGN 1优化了细胞对电离辐射和其他致瘤事件的反应;因此，这种蛋白质的丢失增加了小鼠的肿瘤负荷。
We report that loss of HMGN1, a nucleosome-binding protein that alters the compaction of the chromatin fiber, increases the cellular sensitivity to ionizing radiation and the tumor burden of mice. The mortality and tumor burden of ionizing radiation-treated Hmgn1(-/-) mice is higher than that of their Hmgn1(+/+) littermates. Hmgn1(-/-) fibroblasts have an altered G(2)-M checkpoint activation and are hypersensitive to ionizing radiation. The ionizing radiation hypersensitivity and the aberrant G(2)-M checkpoint activation of Hmgn1(-/-) fibroblasts can be reverted by transfections with plasmids expressing wild-type HMGN1, but not with plasmids expressing mutant HMGN proteins that do not bind to chromatin. Transformed Hmgn1(-/-) fibroblasts grow in soft agar and produce tumors in nude mice with a significantly higher efficiency than Hmgn1(+/+) fibroblasts, suggesting that loss of HMGN1 protein disrupts cellular events controlling proliferation and growth. Hingn1(-/-) mice have a higher incidence of multiple malignant tumors and metastases than their Hmgn1(+/+) littermates. We suggest that HMGN1 optimizes the cellular response to ionizing radiation and to other tumorigenic events; therefore, loss of this protein increases the tumor burden in mice.