NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

Purinoceptors. Some Ap 4 A-mediated transcriptional changes could also involve externalization of Ap 4 A into the growth medium by exocytosis or from damaged or necrotic cells. This Ap 4 A could then act through cell-surface purinoceptors to modulate known signaling pathways leading to changes in gene expression [143] . All known P2 receptor subtypes except P2X2, P2X3, P2X6, P2Y4, P2Y12 and P2Y13 were found to be expressed in KBM-7 cells with P2X1, P2X7 and P2Y8 showing slight but significant up-regulation (1.3-2.3-fold) in NuKO cells (S2 and S3 Tables). Several of these are known to be activated by Ap 4 A [144] ; however, measurement of Ap 4 A in the cell-free growth medium showed that there was actually less in the medium taken from NuKO cells (0.11 ± 0.01 pmol/10 6 cells, n = 3) than in that from KBM-7 cells (0.28 ± 0.07 pmol/10 6 cells, n = 3), possibly due to the 5.5-fold up-regulation of the cell surface phosphodiesterase ENPP1, which is known to hydrolyze extracellular diadenosine polyphosphates [3] . Thus, an increased autocrine signaling effect of Ap 4 A seems unlikely.