Participation of Eag1 in tumor relevant pathways

by Bryan Downie
Doctoral thesis
Date of Examination:2009-10-31
Date of issue:2010-01-12
Advisor:Prof. Dr. Ralf Heinrich
Referee:Prof. Dr. Frauke Melchior
Referee:Prof. Dr. Walter Stühmer
Persistent Address: http://dx.doi.org/10.53846/goediss-3483

 

 

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Abstract

English

Ether--go-go-1 (Eag1) is a CNS-localized voltage-gated potassium channel that is found ectopically expressed in a majority of extra-cranial solid tu- mors. While evidence linking Eag1 to tumor biology has been well estab- lished, the mechanisms by which the channel contributes to tumor progres- sion has until recently remained elusive. In this study, we have used in vivo and in vitro techniques to identify Eag1 interactions with HIF-1 regulatory system as a candidate mechanism. Eag1 functionally and physically interacts with HIF prolyl hydoxylases (PHD) and co-immunoprecipitates with ubiquitin and pVHL. Eag1 ubiquitin co- immunoprecipitation is PHD dependent, and Eag1 undergoes proteasomal degradation. Eag1 expression stabilizes HIF and promotes VEGF secretion and angiogenesis in vivo. Our data suggest that Eag1 interferes with the cellular mechanism for main- taining oxygen homeostasis, increasing HIF-1 activity, and thereby VEGF secretion and tumor vascularization.
Keywords: cancer; ion channel; angiogenesis; hypoxia
 
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