Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated EGLN2-mediated [corrected] oxygen-sensing response.
Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated EGLN2-mediated [corrected] oxygen-sensing response.
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DOI：
10.1371/journal.pgen.1000176
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发表时间：
2008-09-05
期刊：
影响因子：
4.5
通讯作者：
Furge KA
中科院分区：
文献类型：
--
作者：
Koeman JM;Russell RC;Tan MH;Petillo D;Westphal M;Koelzer K;Metcalf JL;Zhang Z;Matsuda D;Dykema KJ;Houseman HL;Kort EJ;Furge LL;Kahnoski RJ;Richard S;Vieillefond A;Swiatek PJ;Teh BT;Ohh M;Furge KA
染色体异常，如结构和数量异常，在癌症中是常见的。在癌细胞中已经观察到同源染色体在间期紧密结合的现象，这种现象被称为体细胞染色体配对，但体细胞配对的功能后果尚未确定。基因表达谱研究表明，19号染色体的体细胞配对是肾嗜酸细胞瘤中反复出现的染色体异常，肾嗜酸细胞瘤是成人肾脏的一种肿瘤。体细胞配对与配对区域内基因表达的显著中断有关，并导致调节缺氧诱导因子(HIF)氧依赖降解的关键蛋白Prolyl-羟基酶ELGN2的失控。ELGN2在肾嗜酸细胞瘤中的过表达增加了泛素介导的HIF的破坏，同时抑制了几个HIF靶基因的表达，包括导致死亡的BNIP3L基因。与19号染色体体细胞配对相关的转录变化模仿了DNA扩增后发生的转录变化。因此，除了数量和结构上的染色体异常，染色体空间动力学的改变应该被认为是与肿瘤发生相关的基因组事件。发现EGLN2是一个显着失控的基因，定位于成对的染色体区域，这直接暗示了肾嗜酸细胞瘤生物学中氧感应网络的缺陷。肾嗜酸细胞瘤和嫌色肾细胞癌(RCC)合计约占肾脏切除肿块的10%。然而，与这些肿瘤的发展相关的分子缺陷尚不清楚。在这里，我们利用遗传学和计算分析的最新进展来筛选在肾嗜酸细胞瘤和嫌色肾细胞癌中都存在的染色体异常。我们发现，嫌色肾细胞癌细胞含有额外的19号染色体拷贝，而肾肿瘤细胞含有罕见的染色体异常。这两种染色体异常都会导致EGLN2基因的转录中断，该基因位于19号染色体上，对细胞对氧气水平变化的反应至关重要。在其他类型的肾脏肿瘤中也发现了氧感知缺陷，而EGLN2的鉴定也直接暗示了这些肿瘤中氧感知网络的缺陷。这些发现很重要，因为肾嗜酸细胞瘤中存在的染色体缺陷也可能存在于其他肿瘤细胞中。此外，解除对EGLN2的管制揭示了氧感应的扰动与疾病相关的一种独特方式。
Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase ELGN2, a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of ELGN2 in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma. Together, renal oncocytoma and chromophobe renal cell carcinoma (RCC) account for approximately 10% of masses that are resected from the kidney. However, the molecular defects that are associated with the development of these neoplasias are not clear. Here, we take advantage of recent advances in genetics and computational analysis to screen for chromosomal abnormalities that are present in both renal oncocytoma and chromophobe RCC. We show that while chromophobe RCC cells contain an extra copy of chromosome 19, the renal oncoctyoma cells contain a rarely reported chromosomal abnormality. Both of these chromosomal abnormalities result in transcriptional disruptions of EGLN2, a gene that is located on chromosome 19 and is critical for the cellular response to changes in oxygen levels. Defects in oxygen sensing are found in other types of kidney tumors, and the identification of EGLN2 directly implicates defects in the oxygen-sensing network in these neoplasias as well. These findings are important because the chromosomal defect present in renal oncocytomas may also be present in other tumor cells. In addition, deregulation of EGLN2 reveals a unique way in which perturbations in oxygen-sensing are associated with disease.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.192342099
发表时间：
2002-10-15
影响因子：
11.1
作者：
Ivan, M;Haberberger, T;Kaelin, WG
通讯作者：
Kaelin, WG
影响因子：
50.3
作者：
Lee, S;Nakamura, E;Schlisio, S
通讯作者：
Schlisio, S
DOI：
10.1073/pnas.0407651101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Graveel, C;Su, YL;Woude, GV
通讯作者：
Woude, GV