The objective of this proposal is to continue our studies on understanding the mechanisms of tumor necrosis factor-alpha (TNF??) signaling in cystogenesis. TNF?? through its receptor and through the ability of the receptor associated proteins to form the membrane bound pro-survival complex I as well as the cytoplasmic pro-death complex II help cancer cells to escape apoptosis. The inhibitor of apoptosis (IAP) antagonist, Smac-mimetic, is able to target the above TNF??-mediated complexes to induce cancer cell death. Our studies have suggested that TNF?? can promote ADPKD progression and our preliminary studies have further found: 1) TNF?? is always present in cyst fluid from ADPKD kidneys;2) Loss of polycystin function leads to increased expression of TNF?? receptor I (TNFR-I);3) The components of proteins in complex I and complex II are upregulated in Pkd1 mutant MEK cells;4) Most importantly, TNF?? alone could not induce normal or Pkd1 mutant epithelial cell death even at high concentrations, while, TNF?? together with transiently transfected Smac could induce only Pkd1 mutant cystic epithelial cell death but had no effect on Pkd1 wild type kidney epithelial cells. Furthermore, the following evidence supports the connection between TNF?? and Id2 signaling pathways: 1) TNF?? activates mTOR through IKK? and mTOR regulates the functional differentiation of mammary epithelial cells through regulating the expression of Id2;2) Receptor activator of NF-?B ligand (RANKL), a TNF family molecule, regulates mammary epithelial cell proliferation via Id2 by triggering marked nuclear translocation of Id2. Based on these findings, we hypothesize that: TNF?? and its receptor are able to regulate cystic epithelial cell apoptosis through the membrane bound pro-survival complex I and cytoplasmic pro-death complex II and further regulate cystic epithelial cell proliferation and differentiation through mTOR or RANKL-mediated Id2 signaling. To test our hypothesis, we propose three aims: 1) To Investigate the mechanism(s) of TNF?? signaling in regulation of kidney epithelial cell survival;2) To determine the potential role and mechanism of the IAP antagonist, Smac-mimetic, in regulating TNF??-dependent cystic kidney epithelial cell death;3) To investigate whether TNF?? signaling regulates cystic epithelial cell proliferation and differentiation through mTOR and RANKL mediated Id2 signaling. Accomplishing this project will further elucidate the role of the pathways downstream of the polycystins in cystogenesis and will identify key regulatory components that may serve as effective targets to slow disease progression.
The objective of this proposal is to continue our studies on understanding the mechanisms of tumor necrosis factor-alpha (TNF??) signaling in cystogenesis. Our general hypothesis is that TNF?? through its receptor to form a membrane bound pro-survival complex protects the cystic epithelial cell apoptosis and IAP antagonist, Smac-mimetic, can induce TNF?? dependent cystic epithelial cell death to further prevent cyst expansion/formation. Accomplishing this project will further elucidate the role of the pathways downstream of the polycystins in cystogenesis and will identify key regulatory components that may serve as effective targets to slow disease progression. The information from our studies will be likely to open new avenues in the research of ADPKD and establish the foundation for developing effective therapies of the disease.
|Zhou, Xia; Fan, Lucy X; Peters, Dorien J M et al. (2015) Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD. Hum Mol Genet 24:3982-93|
|Zhou, Julie X; Fan, Lucy X; Li, Xiaoyan et al. (2015) TNFÎ± signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling. PLoS One 10:e0131043|
|Zhang, Hongbing; Wang, Xiaodong; Xu, Kun et al. (2015) 17Î²-estradiol ameliorates oxygen-induced retinopathy in the early hyperoxic phase. Biochem Biophys Res Commun 457:700-5|
|Chen, Li; Zhou, Xia; Fan, Lucy X et al. (2015) Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease. J Clin Invest 125:2399-412|
|Zhou, Xia; Fan, Lucy X; Li, Keguo et al. (2014) SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1. Hum Mol Genet 23:1644-55|
|Tran, Pamela V; Sharma, Madhulika; Li, Xiaogang et al. (2014) Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 102:159-73|
|Zhou, Xia; Fan, Lucy X; Sweeney Jr, William E et al. (2013) Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest 123:3084-98|
|Fan, Lucy X; Zhou, Xia; Sweeney Jr, William E et al. (2013) Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts. J Am Soc Nephrol 24:2010-22|
|Liu, Wei; Fan, Lucy X; Zhou, Xia et al. (2012) HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS One 7:e49418|
|Fan, Lucy X; Li, Xinjian; Magenheimer, Brenda et al. (2012) Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int 81:76-85|
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