The Function Of P15RS And Gdx In The Tumor And Inflammation Related Signaling Pathway

Wnt signaling and NF-?B signaling play critical roles in tumorigenesis and inflammation.Over-activation of Wnt leads to development of several kinds of cancers,such as colon cancer and breast cancer.The dysregulation of NF-?B leads to imbalance of immune system.This thesis is composed of two parts.The first part focuses on the p15RS-mediated regulation of Wnt/?-catenin signaling.The second part reports the regulation of GdX in innate immune response.We previously reported that p15RS(p15INK4b-related sequence),a regulation of nuclear pre-mRNA domain containing protein,inhibited Wnt signaling by interrupting the formation of the ?-catenin/TCF4 complex.However,how p15 RS functions as an intrinsic repressor to repress transcription remains unclear.In this study,we show that p15 RS,through a specific interaction with HDAC2(histone deacetylase 2),a deacetylase that regulates gene transcription,maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where ?-catenin/TCF4 is bound.We observed that histone deacetylase inhibitors impair the ability of p15 RS in inhibiting Wnt/?-catenin signaling.Depletion of HDAC2 markedly disabled p15 RS inhibition ofWnt/?-catenin-mediated transcription.Interestingly,overexpression of p15 RS decreases the level of acetylated histone H3 in the c-MYC promoter.Finally,we demonstrate that p15 RS significantly enhances the association of HDAC2 and TCF4 and enhances the occupancy of HDAC2 to DNA,resulting in the deacetylation of histone H3 and the failure of ?-catenin interaction.We propose that p15 RS acts as an intrinsic transcriptional repressor for Wnt/?-catenin-mediated gene transcription at least partially through recruiting HDAC2 to occupy the promoter and maintaining deacetylated histone H3.In the second part of the thesis,we explored the functions of GdX in the regulation of NF-?B signaling.We found that GdX-deficient mice were resistant to LPS-induced endotoxin shock.In addition,the production of pro-inflammatory cytokines in the serum or tissue of GdX-deficient mice was much less than that of WT mice in response to LPS stimulation.Luciferase assay showed that GdX positively regulates NF-?B signaling.Further study demonstrated that GdX blocked the dephosphorylation process of p65,by disabling its association with T cell protein tyrosine phosphatase-45(TC45),resulting in NF-?B activation.Our findings reveal a critical role of GdX in the regulation of innate immune response,and prompt that GdX is a novel regulator of NF-?B signaling.