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Dual degradation signals control Gli...

Huntzicker, Erik George.

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Dual degradation signals control Gli stability and Hedgehog signaling in tumor formation.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Dual degradation signals control Gli stability and Hedgehog signaling in tumor formation./
作者:	Huntzicker, Erik George.
面頁冊數:	115 p.
附註:	Adviser: Anthony E. Oro.
Contained By:	Dissertation Abstracts International68-12B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3292370
ISBN:	9780549353829

Dual degradation signals control Gli stability and Hedgehog signaling in tumor formation.
Huntzicker, Erik George.

Dual degradation signals control Gli stability and Hedgehog signaling in tumor formation. - 115 p.

Adviser: Anthony E. Oro.

Thesis (Ph.D.)--Stanford University, 2008.

The Hedgehog signaling pathway arose early in the evolution of multicellular animals and is critical for development in most eumetazoan species. This pathway is highly conserved at the level of both pathway structure and biological function, playing roles in body plan establishment, internal organ formation and appendage development. Dysregulation of this pathway in humans can give rise to myriad birth defects and inappropriate activation of the pathway has been implicated in up to a quarter of all human tumors. The Ci/Gli family of proteins mediates the hedgehog transcriptional response. In fact, transgenic overexpression of Gli proteins, notably Gli1 and Gli2, is sufficient to cause basal cell carcinoma (BCC), a human cancer known to be due to uncontrolled hedgehog signaling. However, there is a wide variability in the onset and severity of phenotypes among patients with mutations in the Shh pathway, and a noticeably wide variability of tumor onset in animal models. This suggests the possibility that additional, previously uncharacterized, cellular processes regulate pathway output. Indeed, a unique quality of the Hedgehog pathway is its ability to exert distinct biological effects based on very small changes in pathway activation. The mechanisms which control these finely tuned responses have been the subject of extensive study and it has become clear that numerous mechanisms control the timing, location and strength of pathway activation. Some of these regulatory mechanisms are highly specific to hedgehog signaling, but some, such as regulated protein destruction, are common to many signaling pathways. Indeed, factors controlling protein destruction are critical for the timing of key processes such as the cell cycle, apoptosis and cell fate decisions, with aberrant regulation increasingly found during carcinogenesis. Here I demonstrate that Gli transcription factors are targeted for destruction by the Ubiquitin Proteasome System (UPS). I identify two novel motifs (degrons) that mediate Gli destruction. Furthermore, I show that the Cullin-associated ubiquitin ligases betaTrCP and SPOP control the stability of Gli transcription factors and the activity of vertebrate hedgehog signaling. Finally, I show that Gli protein accumulation correlates with tumor formation and stabilizing mutations in Gli protein dramatically accelerate tumor induction.

ISBN: 9780549353829Subjects--Topical Terms:

1017686
Biology, Cell.

Dual degradation signals control Gli stability and Hedgehog signaling in tumor formation.
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