Jennifer Alagu
National University of Singapore, Singapore
Title: The novel role of tumour suppressor p14ARF in tumour immunology to induce inflammatory response by enhancing SUMOylation
Biography
Biography: Jennifer Alagu
Abstract
Background: Tumour suppressor p14ARF (alternative reading frame) is activated by oncogenic stress to oncogene-induced senescence via activation of p53. The function of ARF is lost in 40% of cancers. Interestingly, loss of ARF has been shown to compound the effect of p53 inactivation highlighting the need to understand the additional functions of ARF. ARF has emerged as a potent up-regulator of global intracellular SUMOylation, independent of p53 activity. However, few targets of ARF-enhanced SUMOylation have been identified and the functional consequences to cancer aetiology remain to be elucidated.
Methods: We employed a novel screening approach combining ARF with SUMO overexpression. Immunoprecipitation of SUMO was performed to identify the proteins SUMOylated in response to ARF by mass spectrometry.
Results: We identified and validated a novel protein target of ARF-enhanced SUMOylation which is a negative regulator of pro-inflammatory transcription factors STAT1 and NF-kB. ARF has been shown to be inducible by IFN-γ and TNF-α, upstream regulators of STAT1 and NF-kB respectively. Our results show that ARF promotes these pro-inflammatory responses by inhibiting this protein by enhancing its SUMOylation status.
Conclusions: Identification of our novel ARF-mediated SUMOylation target reveals ARF’s p53-independent role in the pro-inflammatory processes that are activated by tumour invasion or infection of oncogenic viruses to prevent tumourigenesis. Our findings present a novel role of ARF in tumour immunology and given the exceptionally high incidence of ARF loss reported in human cancers, may aid in the development of new therapeutic opportunities for dysregulations observed in the ARF-SUMOylation pathway.