SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker.
SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker.
复制标题
DOI：
10.18632/oncotarget.1831
复制
发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Avantaggiati ML
中科院分区：
文献类型：
--
作者：
Kolukula VK;Sahu G;Wellstein A;Rodriguez OC;Preet A;Iacobazzi V;D'Orazi G;Albanese C;Palmieri F;Avantaggiati ML
p53基因突变是许多人类癌症的标志。几种p53突变蛋白获得促进癌症进展和转移的能力，这种现象被定义为致癌功能获得（GOF）。GOF p53突变体干扰与肿瘤发生相关的细胞程序的下游靶点仅部分已知。我们先前已经证明，SLC 25 A1（CIC）促进肿瘤发生，而其抑制则使肿瘤生长变钝。我们现在报告，CIC是几个p53突变体的直接转录靶点。我们确定了一种新的突变型p53（mutp 53）和转录因子FOXO-1，这是负责CIC表达水平的调节之间的相互作用。携带mutp 53的肿瘤细胞相对于p53缺失或野生型肿瘤显示出更高的CIC水平，并且CIC活性的抑制减弱了mutp 53驱动的肿瘤生长，部分克服了GOF活性。CIC抑制还增强了铂类药物的化疗潜力。最后，我们发现CIC水平升高预示着以高频率p53突变为特征的肿瘤的生存结局较差。我们的研究结果将CIC确定为mutp 53的新靶点，并暗示使用CIC抑制剂可以提高存活率并降低携带这些类型突变的肿瘤的化疗耐药性，这些突变是最难治的癌症形式之一。
Mutations of the p53 gene hallmark many human cancers. Several p53 mutant proteins acquire the capability to promote cancer progression and metastasis, a phenomenon defined as Gain of Oncogenic Function (GOF). The downstream targets by which GOF p53 mutants perturb cellular programs relevant to oncogenesis are only partially known. We have previously demonstrated that SLC25A1 (CIC) promotes tumorigenesis, while its inhibition blunts tumor growth. We now report that CIC is a direct transcriptional target of several p53 mutants. We identify a novel interaction between mutant p53 (mutp53) and the transcription factor FOXO-1 which is responsible for regulation of CIC expression levels. Tumor cells harboring mutp53 display higher CIC levels relative to p53 null or wild-type tumors, and inhibition of CIC activity blunts mutp53-driven tumor growth, partially overcoming GOF activity. CIC inhibition also enhances the chemotherapeutic potential of platinum-based agents. Finally, we found that elevated CIC levels predict poor survival outcome in tumors hallmarked by high frequency of p53 mutations. Our results identify CIC as a novel target of mutp53 and imply that the employment of CIC inhibitors may improve survival rates and reduce chemo-resistance in tumors harboring these types of mutations, which are among the most intractable forms of cancers.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.6
作者：
Brachova P;Thiel KW;Leslie KK
通讯作者：
Leslie KK
影响因子：
4.3
作者：
Choudhury, Sujata;Kolukula, Vamsi K.;Avantaggiati, Maria Laura
通讯作者：
Avantaggiati, Maria Laura
影响因子：
4.1
作者：
Infantino, Vittoria;Convertini, Paolo;Iacobazzi, Vito
通讯作者：
Iacobazzi, Vito
影响因子：
--
作者：
Mogi A;Kuwano H
通讯作者：
Kuwano H