Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma
Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma
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DOI：
10.1016/j.ccr.2005.07.004
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发表时间：
2005-08-01
期刊：
影响因子：
50.3
通讯作者：
Parada, LF
中科院分区：
文献类型：
--
作者：
Zhu, Y;Guignard, F;Parada, LF
恶性星形细胞瘤是最常见的原发性脑肿瘤，对所有已知的治疗方法都具有耐药性，并且经常含有使p53失活和激活Ras信号的突变。我们已经产生了缺乏p53的小鼠品系，并且含有负调控Ras信号的NF1肿瘤抑制因子的条件等位基因。小鼠发展为恶性星形细胞瘤，具有完全外显性。大多数肿瘤表现出多形性胶质母细胞瘤的特征，并伴有先前在这种肿瘤的人类对应体中描述的信号通路的改变。我们发现肿瘤抑制因子失活的顺序影响了肿瘤的发生，并且肿瘤形成的最早证据定位于大脑中包含能够在体内分化为神经元和胶质细胞的多能干细胞群的区域。
Malignant astrocytoma, the most prevalent primary brain tumor, is resistant to all known therapies and frequently harbors mutations that inactivate p53 and activate Ras signaling. We have generated mouse strains that lack p53 and harbor a conditional allele of the NF1 tumor suppressor that negatively regulates Ras signaling. The mice develop malignant astrocytomas with complete penetrance. The majority of tumors display characteristics of glioblastoma multiforme with concomitant alteration of signaling pathways previously described in the human counterparts of this neoplasm. We find that the sequence of tumor suppressor inactivation influences turnorigenicity and that earliest evidence of tumor formation localizes to regions of the brain that contain a multipotent stem cell population capable of in vivo differentiation into neurons and glia.