Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells

	Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells
	Han MJ 1,3,4; Wang HL 1; Zhang HT 3; Han ZZ[*]1,2,5
刊名	PLOS ONE
	2012
卷号	7 期号:9 页码:e45402
通讯作者	Zhaozhong.han@vanderbilt.edu
合作状况	其它
英文摘要	Background: Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR. Methodology/Principal Findings: Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR. Conclusions/Significance: This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy.
收录类别	SCI
资助信息	This study was supported in part by National Institutes of Health (NIH) grants R01CA127482 (ZH) and P50 CA128323 (J. Gore).
语种	英语
内容类型	期刊论文
源URL	[http://159.226.149.26:8080/handle/152453/10377]
专题	昆明动物研究所_分子免疫生物学昆明动物研究所_动物模型与人类重大疾病机理重点实验室
作者单位	1.Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, United States of America 2.Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America 3.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan Province, China 4.Graduate School, Chinese Academy of Sciences, Beijing, China 5.Vanderbilt-Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
推荐引用方式 GB/T 7714	Han MJ,Wang HL,Zhang HT,et al. Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells[J]. PLOS ONE,2012,7(9):e45402.
APA	Han MJ,Wang HL,Zhang HT,&Han ZZ[*].(2012).Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells.PLOS ONE,7(9),e45402.
MLA	Han MJ,et al."Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells".PLOS ONE 7.9(2012):e45402.