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Rescue of p53 Blockage by the A_2A Adenosine Receptor via a Novel Interacting Protein, Translin-Associated Protein X

Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan (C.-N.S., H.-C.C., J.C., Y.-W.L., H.-L.L., H.-M.C., Y.C.); Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan (H.-C.C., J.C., Y.-W.L., Y.C.); Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (C.-N.S., Y.C.); and Department of Medical Technology, Yuanpei University of Science and Technology, Hsinchu, Taiwan (J.C.)

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 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 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 A_2A-R mutant harboring the seventh transmembrane domain and its C terminus reduced the rescue effect of A_2A-R. 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, 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 A_2A-R, whereas overexpression of TRAX alone caused the same rescue effect as did A_2A-R activation. Results of [³H]thymidine and bromodeoxyuridine incorporation suggested that A_2A-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Because the antimitotic activity is crucial for NGF 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 (epidermal growth factor) to induce neurite outgrowth. We demonstrate that the A_2A-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.

Address correspondence to: Dr. Yijuang Chern, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan. E-mail: bmychern{at}ibms.sinica.edu.tw

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A Tail of Two Signals: The C Terminus of the A_2A-Adenosine Receptor Recruits Alternative Signaling Pathways

Ingrid Gsandtner and Michael Freissmuth
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