Loss of neurofibromatosis-1 and p19ARF cooperate to induce a multiple tumor phenotype
Loss of neurofibromatosis-1 and p19ARF cooperate to induce a multiple tumor phenotype
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DOI：
10.1038/sj.onc.1205632
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发表时间：
2002-07-25
期刊：
影响因子：
8
通讯作者：
Hiebert, SW
中科院分区：
文献类型：
--
作者：
King, D;Yang, GY;Hiebert, SW
神经纤维瘤病-1（NF 1）基因的失活使RAS失调，并与p（53）肿瘤抑制因子的突变或缺失协同诱导肿瘤发生。p19（ARF）在癌基因检查点中作用于p53的上游，以响应激活的RAS和刺激增殖的其他因子而诱导凋亡。因此，我们将p19（ARF-/-）与NF 1（+/-）-小鼠交配，以确定这些基因的缺失是否与肿瘤发生有关。正如NF 1基因敲除小鼠的胚胎致死率所预期的那样，没有出生既缺乏p19（ARF）又缺乏NF 1的小鼠。出乎意料的是，在p19（ARF）无效背景下，NF 1一个等位基因的丢失并没有大大缩短肿瘤形成的时间。观察到的肿瘤类型是p19（ARF）缺失动物的特征，而不是与神经纤维瘤病或NF 1（+/-）/p53（+/-）小鼠相关的肿瘤类型。然而，12只动物中有7只发生了多发性肿瘤，有些还发生了转移。这种多肿瘤表型以前没有观察到p19（ARF）-null小鼠，并建议这些肿瘤抑制因子的损失之间的合作的一种独特形式。
Inactivation of the neurofibromatosis-1 (NF1) gene deregulates RAS and cooperates with mutation or loss of the p(53) tumor suppressor to induce tumorigenesis. p19(ARF) acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19(ARF-/-) to NF1(+/-) -mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19(ARF) and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19(ARF) null background. The tumor types observed were characteristic of p19(ARF) null animals, not those associated with neurofibromatosis or those observed with NF1(+/-)/p53(+/-) mice. However, seven out of 12 animals developed multiple tumors, some With metastases. This multiple tumor phenotype was not previously observed with p19(ARF)-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.