Tumor protein D52 represents a negative regulator of ATM protein levels

Abstract

Tumor protein D52 (TP D52) is a coiled-coil motif bearing hydrophilic polypeptide known to be overexpressed in cancers of diverse cellular origins. Increased TP D52 expression is associated with increased proliferation and invasive capacity in different cell types. Recent studies have reported a correlation between TPD52 transcript levels and G2 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 TP D52 in DNA damage response, and found that increased TP D52 expression in breast cancer and TP D52-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. TP D52-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 TP D52 were detected by GST pull-down and co-immunoprecipitation assays. We also identified the interaction domains involved in this binding as TP D52 residues 111-131, and ATM residues 1-245 and 772-1102. Taken together, our results suggest that TP D52 may represent a novel negative regulator of ATM protein levels. © 2013 Landes Bioscience.