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Regulation of STAT6, STAT3 and STAT1 by the Cytoplasmic Tail of Polycystin-1, the Protein Affected in Polycystic Kidney Disease

Shivakumar, Vasanth
http://rave.ohiolink.edu/etdc/view?acc_num=kent1176482324

Abstract Details

2007, PHD, Kent State University, College of Arts and Sciences / Department of Biological Sciences.
Autosomal Dominant Polycystic Kidney Disease a monogenic inherited human disease causing renal epithelial cells to proliferate forming fluid-filled cysts resulting in renal failure. Currently, no treatment exists to prevent or slower cyst formation, and most ADPKD patients require renal transplantation or life-long hemodialysis for survival. Mutations in either PKD1 or PKD2, are the underlying cause of ADPKD, with PKD1 mutations accounting for over 85% of the cases. Polycystin-1 (PC1) is an integral membrane glycoprotein containing 4302 amino acids with putative extracytoplasmic ligand-binding domains, but no physiological ligand has been identified to date. It has 11 transmembrane domains with an extracytoplasmic region of ~3000 amino acids and a cytoplasmic tail of ~200 amino acids. Many signaling pathways has been implicated to play a causative role for ADPKD but none show a clear mechanism. The study of STAT6, P100 and the PC1 tail using reporter assays, binding experiments, and immunohistochemistry suggested a model where the PC1 tail is cleaved due to loss of fluid flow, which triggers the nuclear translocation the constitutive trimeric complex comprising of the cleaved PC1 tail, STAT6 and P100 in renal epithelial cells. Introduction of C-terminus and the complete PC1 tail mRNA in zebra fish embryos resulted in cyst formation in their pronephric duct. Increased STAT6, P100 and PC1 tail staining in ADPKD kidney tissue sections also proved the importance of this pathway in stimulating cystogenesis. The membrane anchored PC1 tail was sufficient to activate constitutive pY-STAT3 and whereas the cleaved PC1 tail stimulated IFN-gamma stimulated reporter. This brings out a model where the PC1 can act as a molecular switch whereby it can regulate different STAT pathways depending on cellular conditions. Constitutive activation of STAT3 by normal PC1 may suggest the active STAT pathway under normal condition. Cleavage of the PC1 tail due to renal injury changes the function of the tail as a transcriptional co-activator which may now either activate STAT6 which would lead to proliferation or STAT1 or STAT3 leading to apoptosis. Inhibitors of the pathways that are activated in ADPKD can prove to be potential therapies for the disease.
Thomas Weimbs (Advisor)
98 p.
POLYCYSTIN; CILIA; P100; STAT6; STAT3; STAT1; IL4; IFN; KIDNEY; POLYCYSTIC KIDNEY DISEASE

Recommended Citations

Citations

  • Shivakumar, V. (2007). Regulation of STAT6, STAT3 and STAT1 by the Cytoplasmic Tail of Polycystin-1, the Protein Affected in Polycystic Kidney Disease [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176482324

    APA Style (7th edition)

  • Shivakumar, Vasanth. Regulation of STAT6, STAT3 and STAT1 by the Cytoplasmic Tail of Polycystin-1, the Protein Affected in Polycystic Kidney Disease. 2007. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1176482324.

    MLA Style (8th edition)

  • Shivakumar, Vasanth. "Regulation of STAT6, STAT3 and STAT1 by the Cytoplasmic Tail of Polycystin-1, the Protein Affected in Polycystic Kidney Disease." Doctoral dissertation, Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176482324

    Chicago Manual of Style (17th edition)

kent1176482324
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© 2007, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.