title: Expression of TIP-1 confers radioresistance of malignant glioma cells.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Miaojun
authors.initials: M
authors.lastname: Han
authors.forename: Hailun
authors.initials: H
authors.lastname: Wang
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Zhang
authors.forename: Zhaozhong
authors.initials: Z
authors.lastname: Han
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000378:metabolism; D034622:RNA Interference; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C405928:CDK5RAP3 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C421249:TAX1BP3 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020727:ADP-Ribosylation Factors