The cyclin D1-CDK4 oncogenic interactome enables identification of potential novel oncogenes and clinical prognosis
The cyclin D1-CDK4 oncogenic interactome enables identification of potential novel oncogenes and clinical prognosis
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DOI：
10.4161/15384101.2014.946850
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发表时间：
2014-09-15
期刊：
影响因子：
4.3
通讯作者：
Sicinski, Piotr
中科院分区：
文献类型：
--
作者：
Jirawatnotai, Siwanon;Sharma, Samanta;Sicinski, Piotr
细胞周期蛋白D1及其催化伙伴CDK4的过表达经常见于人类癌症。我们在人乳腺癌细胞系MCF 7中构建了cyclin D1和CDK4蛋白相互作用网络，并鉴定了新的CDK4蛋白伴侣。在CDK4相互作用中，我们观察到几种蛋白质在蛋白质折叠和复杂组装中发挥作用。CDK4的新伙伴之一是FKBP 5，我们发现它是维持癌细胞中CDK4水平所必需的。对人类癌症中扩展的细胞周期蛋白D1癌症相互作用组和体细胞拷贝数改变的综合分析将BAIAPL 21鉴定为潜在的新型人类癌基因。我们观察到，在几种人类肿瘤类型中，与正常组织相比，BAIAPL 21以更高的水平表达。BAIAPL 21的强制过表达增强了锚定非依赖性生长，增加了癌细胞的集落形成，并强烈增强了细胞在体内形成肿瘤的能力。最后，我们得出了一个聚合表达评分（AES），它量化了给定肿瘤中所有细胞周期蛋白D1相互作用因子的表达。我们观察到AES在ER阳性乳腺癌患者中具有预后价值。这些研究说明了分析与癌症有关的蛋白质的相互作用组以发现潜在的致癌基因或允许更好的癌症预后的效用。
Overexpression of cyclin D1 and its catalytic partner, CDK4, is frequently seen in human cancers. We constructed cyclin D1 and CDK4 protein interaction network in a human breast cancer cell line MCF7, and identified novel CDK4 protein partners. Among CDK4 interactors we observed several proteins functioning in protein folding and in complex assembly. One of the novel partners of CDK4 is FKBP5, which we found to be required to maintain CDK4 levels in cancer cells. An integrative analysis of the extended cyclin D1 cancer interactome and somatic copy number alterations in human cancers identified BAIAPL21 as a potential novel human oncogene. We observed that in several human tumor types BAIAPL21 is expressed at higher levels as compared to normal tissue. Forced overexpression of BAIAPL21 augmented anchorage independent growth, increased colony formation by cancer cells and strongly enhanced the ability of cells to form tumors in vivo. Lastly, we derived an Aggregate Expression Score (AES), which quantifies the expression of all cyclin D1 interactors in a given tumor. We observed that AES has a prognostic value among patients with ER-positive breast cancers. These studies illustrate the utility of analyzing the interactomes of proteins involved in cancer to uncover potential oncogenes, or to allow better cancer prognosis.