title: Tumor protein D52 represents a negative regulator of ATM protein levels.
abstract: Tumor protein D52 (TPD52) is a coiled-coil motif bearing hydrophilic polypeptide known to be overexpressed in cancers of diverse cellular origins. Increased TPD52 expression is associated with increased proliferation and invasive capacity in different cell types. Recent studies have reported a correlation between TPD52 transcript levels and G 2 chromosomal radiosensitivity in lymphocytes of women at risk of hereditary breast cancer, and that TPD52 knockdown significantly reduced the radiation sensitivity of multiple cancer cell lines. In this study, we investigated possible roles for TPD52 in DNA damage response, and found that increased TPD52 expression in breast cancer and TPD52-expressing BALB/c 3T3 cells compromised ATM-mediated cellular responses to DNA double-strand breaks induced by γ-ray irradiation, which was associated with downregulation of steady-state ATM protein, but not transcript levels, regardless of irradiation status. TPD52-expressing 3T3 cells also showed significantly increased radiation sensitivity compared with vector cells evaluated by clonogenic assays. Furthermore, direct interactions between exogenous and endogenous ATM and TPD52 were detected by GST pull-down and co-immunoprecipitation assays. We also identified the interaction domains involved in this binding as TPD52 residues 111-131, and ATM residues 1-245 and 772-1102. Taken together, our results suggest that TPD52 may represent a novel negative regulator of ATM protein levels.
authors: Molecular Oncology Laboratory; Children's Cancer Research Unit; Kids Research Institute; The Children's Hospital at Westmead; Sydney, NSW Australia; The University of Sydney Discipline of Paediatrics and Child Health; The Children's Hospital at Westmead; Sydney, NSW Australia.
authors: Yuyan
authors: Y
authors: Chen
authors: Alvin
authors: A
authors: Kamili
authors: Jayne R
authors: JR
authors: Hardy
authors: Guy E
authors: GE
authors: Groblewski
authors: Kum Kum
authors: KK
authors: Khanna
authors: Jennifer A
authors: JA
authors: Byrne
mesh_terms: D016475:3T3 Cells; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair; D015536:Down-Regulation / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C114751:TPD52 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DNA damage response; TPD52; cancer; protein-protein interaction
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