Received for publication November 29, 2005.
Revised April 12, 2006.
Accepted for publication April 14, 2006.

Rescue of p53 blockage by the A_2A adenosine receptor via a novel interacting protein, Translin-associated protein X

Abstract

Blockage of the p53 tumor suppressor has been found to impair nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. We report herein that such impairment could be rescued by stimulation of the A_2A adenosine receptor (A_2A-R), a G protein-coupled receptor implicated in neuronal plasticity. The A_2A-R-mediated rescue occurred in the presence of PKC inhibitors or of PKA inhibitors, and in a PKA-deficient PC12 variant. Thus, neither PKA nor PKC was involved. In contrast, expression of a truncated A_2A-R mutant harboring the 7th transmembrane domain and its C terminus reduced A_2A-R's rescue effect. Using the cytoplasmic tail of the A_2A-R as bait, a novel-A_2A-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, co-immunoprecipitation, and colocalization of these two molecules in the brain. Importantly, reduction of TRAX using an antisense construct suppressed A_2A-R's rescue effect, whereas overexpression of TRAX alone caused the same rescue effect as did A_2A-R activation. Results of ³H-thymidine and BrdU incorporation suggested that A_2A-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Since the antimitotic activity is crucial for NGF's function, the A_2A-R might exert its rescue effect through a TRAX-mediated antiproliferative signal. This antimitotic activity of the A_2A-R also enables a mitogenic factor (EGF) to induce neurite outgrowth. Collectively, we demonstrate that the A_2A-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.

Key words: Adenosine, Purinergic, cAMP, Protein Kinase A, Protein Kinase C, Oncogenes, Caffeine

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