THESIS DEFENSE — PUBLIC SEMINAR: TUMOR SUPPRESSOR P14ARF ENHANCES IFNγ-ACTIVATED IMMUNE RESPONSE BY INHIBITING PIAS1 VIA SUMOYLATION

Start Date & Time: 
Monday, 9 April, 2018 - 09:30
End Date & Time: 
Monday, 9 April, 2018 - 10:30
Venue: 

Amphitheatre, Level 2, Duke-NUS

Speaker: 
Speaker Details: 

JENNIFER ALAGU
IBM PhD PROGRAM ( INTAKE 2013)

Synopsis: 

Recent studies have revealed that tumor suppressor p14ARF (ARF), which is lost in 40% of cancers, plays a significant role in upregulating the innate immune response. However, the underlying mechanisms are unclear. ARF is also known to promote protein SUMOylation. From systematic screening of proteins SUMOylated by ARF, I uncovered a mechanism by which ARF promotes IFNγ-activated response by inhibiting PIAS1 - a potent inhibitor of IFN-activated STAT1, via enhancing SUMOylation.

First, I identified PIAS1 as a novel ARF-binding partner and SUMOylation target and that SUMO-modification serves to impede the repressive activity of PIAS1 on IFNγ-induced transcription. Second, ARF overexpression significantly enhanced the transcriptional activation of IFN-stimulated response elements (ISRE)- and IFNγ-activated site (GAS)-luciferase in response to IFNγ, but not to IFNα. This function of ARF was dependent on the ability of ARF to promote PIAS1 SUMOylation. Third, IFNγ enhanced rapid PIAS1 SUMOylation in an ARF-dependent manner. Fourth, in response to IFNγ, ARF overexpression enhanced the expression of IFNγ-response genes that are known to be repressed by PIAS1, whereas depletion of ARF reduced induction of these genes.

Our findings, suggest that tumor cells with loss of ARF may have incapacitated ability to adequately detect and respond to external inflammatory stimuli, which could promote sustained inflammation and accelerate tumorigenesis.