MYCN 的靶向表达在转基因小鼠中引发神经母细胞瘤。
Targeted expression of MYCN causes neuroblastoma in transgenic mice.
作者信息
Weiss W A, Aldape K, Mohapatra G, Feuerstein B G, Bishop J M
机构信息
G.W. Hooper Foundation, and Department of Neurology, University of California, San Francisco 94143-0552, USA.
出版信息
EMBO J. 1997 Jun 2;16(11):2985-95. doi: 10.1093/emboj/16.11.2985.
Abstract
The proto-oncogene MYCN is often amplified in human neuroblastomas. The assumption that the amplification contributes to tumorigenesis has never been tested directly. We have created transgenic mice that overexpress MYCN in neuroectodermal cells and develop neuroblastoma. Analysis of tumors by comparative genomic hybridization revealed gains and losses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In addition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigenesis by the transgene. Our results provide direct evidence that MYCN can contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further study of the pathogenesis and therapy of neuroblastoma.
摘要
原癌基因MYCN在人类神经母细胞瘤中常发生扩增。扩增导致肿瘤发生这一假设从未得到直接验证。我们构建了在神经外胚层细胞中过表达MYCN并发生神经母细胞瘤的转基因小鼠。通过比较基因组杂交分析肿瘤发现，至少七个染色体区域存在增减变化，所有这些区域与在人类神经母细胞瘤中检测到的类似异常具有同源性。此外，我们还表明，MYCN剂量增加或肿瘤抑制基因NF1或RB1中的任何一个存在缺陷，均可增强转基因导致的肿瘤发生。我们的结果提供了直接证据，证明MYCN可促成神经母细胞瘤的发生，表明神经母细胞瘤发生过程中涉及的遗传事件可能按不止一种时间顺序具有致瘤性，并为进一步研究神经母细胞瘤的发病机制和治疗提供了一个模型。
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本文引用的文献
1
Lessons from hereditary colorectal cancer.遗传性结直肠癌的经验教训。
Cell. 1996 Oct 18;87(2):159-70. doi: 10.1016/s0092-8674(00)81333-1.
2
High-resolution mapping of a 130-kb core region of the MYCN amplicon in neuroblastomas.神经母细胞瘤中MYCN扩增子130kb核心区域的高分辨率图谱。
Genomics. 1996 Feb 15;32(1):97-103. doi: 10.1006/geno.1996.0081.
3
Cdc25 cell-cycle phosphatase as a target of c-myc.细胞周期蛋白磷酸酶Cdc25作为c-myc的一个靶点。
Nature. 1996 Aug 8;382(6591):511-7. doi: 10.1038/382511a0.
4
Co-amplification and concomitant high levels of expression of a DEAD box gene with MYCN in human neuroblastoma.在人类神经母细胞瘤中，一个DEAD盒基因与MYCN共同扩增并伴随高水平表达。
Genes Chromosomes Cancer. 1995 Nov;14(3):196-203. doi: 10.1002/gcc.2870140307.
5
Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras.人黑色素瘤和神经母细胞瘤细胞系中NF1基因的失活，而不影响GTP.Ras的调节。
Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5539-43. doi: 10.1073/pnas.90.12.5539.
6
Neurofibromatosis type 1 gene mutations in neuroblastoma.神经母细胞瘤中的1型神经纤维瘤病基因突变。
Nat Genet. 1993 Jan;3(1):62-6. doi: 10.1038/ng0193-62.
7
Neuroblastoma in a transgenic mouse carrying a metallothionein/ret fusion gene.携带金属硫蛋白/ret融合基因的转基因小鼠中的神经母细胞瘤
Br J Cancer. 1993 Mar;67(3):504-7. doi: 10.1038/bjc.1993.94.
8
Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification.神经母细胞瘤中p53基因的突变及其与N-myc扩增的关系。
Cancer Res. 1993 Sep 1;53(17):4053-8.
9
Low frequency of the p53 gene mutations in neuroblastoma.神经母细胞瘤中p53基因突变的低频率
Cancer. 1994 Jun 15;73(12):3087-93. doi: 10.1002/1097-0142(19940615)73:12<3087::aid-cncr2820731230>3.0.co;2-9.
10
Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.Nf1基因靶向突变杂合小鼠的肿瘤易感性。
Nat Genet. 1994 Jul;7(3):353-61. doi: 10.1038/ng0794-353.
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