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.

IPA 1 prediction of upstream regulatory factors IPA 1 prediction of key upstream regulators for the DEGs suggests numerous factors controlling large sets of down-regulated genes with fewer factors controlling small groups of up-regulated genes. Of the top 100 most significant potential regulators, 97 are proposed to contribute to gene down-regulation (S8 Table) although the total number of genes that are up-and downregulated is similar. The inter-relationships between the top-ranked transcription factors implicated in gene down-regulation and their major identified targets are shown in Fig 9. The functions of several of these have already been described. In addition, CNOT7 (hCAF1) is a STAT1-binding negative regulator of Type I and Type II IFN signalling [133] , while the transcription factor IRF3 is an important responder to PRR activation ( Fig 5) and co-operates with NF-κB and IRF7 in the transcription of IRF3-and NF-κB-dependent genes [113] . SP1 controls the transcription of multiple genes, many of which have been described as promoting the 'hallmarks' of cancer: proliferation, independence from growth signals, avoidance of apoptosis and immune destruction, invasion and metastasis, and angiogenesis. It is overexpressed in many tumors, making it a target for chemotherapy [134, 135] .