2.2.3. Inhibition of Antiviral Responses by RAS-Regulated Factors

Oncogenic RAS may also regulate OV replication through effects on additional oncogenes. For example, the enhanced replication of oncolytic Newcastle disease virus (NDV) depends on RAC1 in highly-malignant RAS-transformed keratinocytes [52]; and RAC1 is a downstream effector of oncogenic RAS [53,54]. In addition, the CDC25 phosphatase, a RAF-regulated oncogene [55], negatively regulates TBK1 through dephosphorylation, inhibiting RIG-I-mediated induction of IFN [56]. Moreover, while oncogenic KRAS increases PKC-βII expression in a murine colon-cancer model [57], this enzyme phosphorylates and inhibits RIG-I, and enhances VSV replication in different cellular settings [58]. The notion of a functional interaction between MDA-5 and oncogenic-RAS is exemplified by the suppression of pro-apoptotic effects of MDA-5 overexpression by either oncogenic RAS or RAF [59]. An additional mode of action is observed for the MYC oncogene, which functions as a crucial effector of oncogenic KRAS, [60,61] and represses, together with the transcriptional repressor MIZ, the type I IFN pathway [61]. Interestingly, inactivation of the tumor suppressor phosphatase and tensin homologue (PTEN), which among its well-documented malignancy-promoting activities [62] accelerates tumorigenesis induced by KRAS [63], results in increased phosphorylation of Ser97 in IRF3, in the negative regulation of IRF-mediated IFN induction upon viral challenge, and in increased viral (VSV) replication [64].

Together, the above-mentioned examples (Section 2.2) demonstrate the ability of oncogenic signaling to interfere with all steps of the antiviral response continuum, including PRR-mediated PAMP recognition, IFN induction, JAK/STAT signaling and ISG expression.
