RT Journal Article SR Electronic T1 Rescue of p53 Blockage by the A2A Adenosine Receptor via a Novel Interacting Protein, Translin-Associated Protein X JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 454 OP 466 DO 10.1124/mol.105.021261 VO 70 IS 2 A1 Chung-Nan Sun A1 Hsiao-Chun Cheng A1 Jui-ling Chou A1 Shen-Yang Lee A1 Ya-Wen Lin A1 Hsing-Lin Lai A1 Hui-Mei Chen A1 Yijuang Chern YR 2006 UL http://molpharm.aspetjournals.org/content/70/2/454.abstract AB Blockage of the p53 tumor suppressor has been found to impair nerve growth factor (NGF)-induced neurite outgrowth in PC-12 cells. We report herein that such impairment could be rescued by stimulation of the A2A adenosine receptor (A2A-R), a G protein-coupled receptor implicated in neuronal plasticity. The A2A-R-mediated rescue occurred in the presence of protein kinase C (PKC) inhibitors or protein kinase A (PKA) inhibitors and in a PKA-deficient PC-12 variant. Thus, neither PKA nor PKC was involved. In contrast, expression of a truncated A2A-R mutant harboring the seventh transmembrane domain and its C terminus reduced the rescue effect of A2A-R. Using the cytoplasmic tail of the A2A-R as bait, a novel-A2A-R-interacting protein [translin-associated protein X (TRAX)] was identified in a yeast two-hybrid screen. The authenticity of this interaction was verified by pull-down experiments, coimmunoprecipitation, and colocalization of these two molecules in the brain. It is noteworthy that reduction of TRAX using an antisense construct suppressed the rescue effect of A2A-R, whereas overexpression of TRAX alone caused the same rescue effect as did A2A-R activation. Results of [3H]thymidine and bromodeoxyuridine incorporation suggested that A2A-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Because the antimitotic activity is crucial for NGF function, the A2A-R might exert its rescue effect through a TRAX-mediated antiproliferative signal. This antimitotic activity of the A2A-R also enables a mitogenic factor (epidermal growth factor) to induce neurite outgrowth. We demonstrate that the A2A-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.