Melanoma susceptibility and cell cycle genes in Xiphophorus hybrids
Melanoma susceptibility and cell cycle genes in Xiphophorus hybrids
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DOI：
10.1002/mc.20343
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发表时间：
2007-08-01
影响因子：
4.6
通讯作者：
Nairn, Rodney S.
中科院分区：
文献类型：
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作者：
Butler, Andrew P.;Trono, David;Nairn, Rodney S.
剑尾鱼种间杂种提供了自发和诱导性黑色素瘤发生的遗传定义模型。在这两个模型中，不同株系的回交F-1杂种的X。maculatus和X helleri为一个X. helleri亲鱼导致黑色素瘤易感性分离，符合孟德尔双基因遗传模型。性连锁的Xmrk癌基因是黑色素瘤的发展所需的两个十字架。剑尾鱼CDKN 2 A/B基因与哺乳动物CDKN 2 A/B细胞周期蛋白依赖性激酶抑制剂（p16和p15）同源，是黑色素瘤易感基因。在该模型中，肿瘤易感性以CDKN 2A/B的同源性从复发性X细胞分离。回交杂种中helleri亲本。我们发现CDKN 2 A/B mRNA和蛋白在黑色素瘤中高度过表达。由于CDKN 2A/B的p13蛋白产物是G1检查点的假定调节剂，因此我们研究了剑尾鱼G1检查点对照的其他组分的表达。通过实时PCR分析，视网膜母细胞瘤基因（RB）在肿瘤和黑化皮肤中的表达始终是正常组织的两倍，表明RB在剑尾鱼黑色素瘤中的过表达并不受CDKN 2 A/B的下调。我们还发现肿瘤中CDKN 2 A/B和Xmrk RNA的定量水平之间存在显著相关性，表明Xmrk和CDKN 2 A/B表达之间存在功能关系。虽然X. helleri CDKN 2 A/B蛋白含有一个非保守性取代，其生化功能似乎没有明显缺陷。这些研究表明，在剑尾鱼黑色素瘤中，CDKN 2 A/B在功能上不足以在Xmrk存在下介导细胞周期停滞。(c)2007 Wiley-Liss，Inc.
Xiphophorus interspecies hybrids provide genetically defined models of both spontaneous and inducible melanomagenesis. In both models, backcrossing F-1 hybrids of different strains of X. maculatus and X helleri to a X. helleri parental fish results in segregation of melanoma susceptibility, fitting a Mendelian two-gene inheritance model. The sex-linked Xmrk oncogene is required for melanoma development in both crosses. The Xiphophorus CDKN2A/B gene, which is homologous to mammalian CDKN2A/B cyclin-dependent kinase inhibitors (p16 and p15), is a candidate melanoma susceptibility gene. In this model, tumor susceptibility segregates with homozgyosity for CDKN2A/B from the recurrent X. helleri parent in backcross hybrids. We found that both CDKN2A/B mRNA and protein are highly overexpressed in melanoma. Because the p13 protein product of CDKN2A/B is a putative regulator of the G1 checkpoint, we investigated expression of other components of Xiphophorus G1 checkpoint control. By real-time PCR analysis, retinoblastoma gene (RB) is consistently expressed twofold higher in both tumors and melanized skin than in normal tissue, indicating that RB is not downregulated by the overexpression of CDKN2A/B in Xiphophorus melanoma. We also found a significant correlation between the quantitative level of CDKN2A/B and Xmrk RNA in tumors, suggesting a functional relationship between Xmrk and CDKN2A/B expression. Although X. helleri CDKN2A/B protein contains a non-conservative substitution, the biochemical function appears to show little overt defect. These studies indicate that in Xiphophorus melanoma, CDKN2A/B is functionally insufficient to mediate cell-cycle arrest in the presence of Xmrk. (c) 2007 Wiley-Liss, Inc.