The ATDC (TRIM29) Protein Binds p53 and Antagonizes p53-Mediated Functions

Abstract

The ataxia telangiectasia group D-complementing (ATDC) gene product, also known as TRIM29, is a member of the tripartite motif (TRIM) protein family. ATDC has been proposed to form homo- or heterodimers and to bind nucleic acids. In cell cultures, ATDC expression leads to rapid growth and resistance to ionizing radiation (IR), whereas silencing of ATDC expression decreases growth rates and increases sensitivity to IR. Although ATDC is overexpressed in many human cancers, the biological significance of ATDC overexpression remains obscure. We report here that ATDC increases cell proliferation via inhibition of p53 nuclear activities. ATDC represses the expression of p53-regulated genes, including p21 and NOXA. Mechanistically, ATDC binds p53, and this interaction is potentially fine-tuned by posttranslational acetylation of lysine 116 on ATDC. The association of p53 and ATDC results in p53 sequestration outside of the nucleus. Together, these results provide novel mechanistic insights into the function of ATDC and offer an explanation for how ATDC promotes cancer cell proliferation.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank J. Murnane (University of California at San Francisco) for the ATDC cDNA, X. F. Wang (Duke) for p21 promoter reporter plasmids, J. Wu (Moffitt Cancer Center) for the c-Ha-Ras expression plasmid, J. Neveu and R. Robinson (Harvard) for LC-MS/MS, and the Moffitt Cancer Center Core Facility for their technical assistance.

This study was supported by grants to E.S. from the National Institutes of Health (GM81650), the AHA (0755298), and the Kaul Foundation.

Z.Y. and E.S. conceived the project. Z.Y. performed most of the experiments with substantial support and help from A.V., L.P., D.C., M.G., E.M.S., J.C., and W.S.L. E.S. wrote the first draft of the manuscript with subsequent contributions from all authors.