Pathogenic Activation of STAT3 in Autosomal Dominant Polycystic Kidney Disease
- Degree Grantor:
- University of California, Santa Barbara. Molecular, Cellular & Developmental Biology
- Degree Supervisor:
- Thomas Weimbs
- Place of Publication:
- [Santa Barbara, Calif.]
- Publisher:
- University of California, Santa Barbara
- Creation Date:
- 2013
- Issued Date:
- 2013
- Topics:
- Biology, Molecular and Biology, Cell
- Keywords:
- Renal,
Polycystic,
Src,
CAMP,
STAT3, and
ADPKD - Genres:
- Online resources and Dissertations, Academic
- Dissertation:
- Ph.D.--University of California, Santa Barbara, 2013
- Description:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited disease induced by loss of both functional copies of either Polycystin-1 or Polycystin-2. Pathogenic symptoms of the disease become apparent in mid-life. As the disease progresses normal renal tubule tissue is progressively replaced by fluid-filled epithelial- lined cysts. This corresponds with a decline in kidney filtration function, eventually leading to kidney failure, which is addressed by either kidney transplant or lifelong dialysis. While these treatments are expensive they are the only options currently available to prevent ADPKD from being a fatal disease. To counter these grim prospects, my dissertation research has focused on the molecular mechanisms responsible for ADPKD disease development. We report that the transcription factor STAT3 is a significant player in ADPKD. While Polycystin-1 activates STAT3 transcription, a novel disease associated PC1 cleavage event (P15) prevents this from occurring in ADPKD. Alternatively, the disease-associated PC1-P30 cleavage product co-activates and enhances STAT3 transcription. Surprisingly, we also report significantly elevated levels of SOCS3 in ADPKD. SOCS3 inhibits JAK2-dependent STAT3 activity, indicating that the aberrantly activated STAT3 associated with ADPKD is from a JAK-independent source. Indeed, we report the novel finding that the Vasopressin 2 receptor activates Src and its ability to transcriptionally activate STAT3. This occurs in a cAMP-dependent and JAK-independent manner, and this is further enhanced by PC1-P30. This is the first report of a contiguous, plasma membrane to nucleus signaling pathway implicated in ADPKD.
- Physical Description:
- 1 online resource (116 pages)
- Format:
- Text
- Collection(s):
- UCSB electronic theses and dissertations
- Other Versions:
- http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3559837
- ARK:
- ark:/48907/f3d798jt
- ISBN:
- 9781303052811
- Catalog System Number:
- 990039788380203776
- Copyright:
- Jeff Talbot, 2013
- Rights:
In Copyright
- Copyright Holder:
- Jeff Talbot
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