p53 is widely known as 'the guardian of the genome'due to its ability to activate either cell cycle arrest or apoptosis in response to DNA damage. This project has uncovered a novel role of p53 cell stress responses in enforcing innate immunity by transcriptional upregulation of IRF9, a central component of the type I interferon (IFN) response. Recent evidence from our studies and others indicates that p53 also directly upregulates several target genes in pathways that play a major role in innate immunity including toll-like receptors (TLRs), IFNregulatory factors (IRFs), IFN-stimulated genes (ISGs) and tumor necrosis factor alpha (TNF-a). Within this project, we discovered a novel p53 target gene, CDIP (Cell Death Involved p53 target), which markedly upregulates p53 dependent expression of TNF-a, and promotes TNF-a apoptosis over survival cell fate decisions. We plan to continue our investigations addressing these novel directions in p53 biology.
Aim 1 of this proposal is directed toward investigating the contribution of p53 dependent expression of these newly identified target genes to the innate antiviral immune response including a miRNA component of this response identified by us to play a role as well. We will explore with Projects 2 and 3, our findings that type I IFNs enhance protein levels by a non-transcriptional mechanism as well as the posttranslational modifications involved. We will also determine the ability of MDM2 inhibitors, which increase p53 at the protein level to enhance p53-dependent innate antiviral responses in vitro and in vivo.
In Aim 2 we will investigate mechanisms by which CDIP enforces TNF-a induced apoptosis over survival and its specific role in TNF-a growth inhibition of human tumor cells. We will also utilize a tandem affinity purification strategy to identify CDIP Interacting proteins and collaborate with Project 2 to solve the novel structure of this molecule. We have evidence for feasibility of generating a CDIP knockout mouse that should help to elucidate CDIP tissue expression and any developmental perturbations due to loss of function on development, as well as how loss of CDIP function affects chemo/irradiation and TNF-a sensitivity.
In Aim 3, we plan to integrate these investigations toward elucidating how p53 innate immune functions through cytokine signaling impact tumorigenesis in chemical carcinogenesis models in which endogenous IFNs and TNF-a are known to inhibit tumor formation. MDM2 small molecule antagonists will be applied to dissect p53 tumor suppressor functions in tumor initiation and progression. These investigations will be aided by continuing monthly meetings and collaborative interactions involving experienced investigators within the Program, each of whom is focused on studying novel aspects of p53 regulation and effectors.
The overall relevance of this Project is that it explores previously unrecognized functions of the highly evolutionarily conserved p53 protein in innate immunity. These functions may contribute to its tumor suppressor role by enforcing cytokine signaling known to inhibit tumor progression as well as contribute along with p53 pro-apoptotic signaling to innate antiviral immunity. Studies within this project are also designed to assess whether MDM2 antagonists can be utilized to further target these p53 dependent functions against cancer and viral infection.
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|Mungamuri, Sathish Kumar; Qiao, Rui F; Yao, Shen et al. (2016) USP7 Enforces Heterochromatinization of p53 Target Promoters by Protecting SUV39H1 from MDM2-Mediated Degradation. Cell Rep 14:2528-37|
|Muñoz-Fontela, César; Mandinova, Anna; Aaronson, Stuart A et al. (2016) Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 16:741-750|
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