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Retinoblastoma protein modulates gan...

Qiu, Wei.

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Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity./
作者:	Qiu, Wei.
面頁冊數:	159 p.
附註:	Adviser: Zhi-Xiong Jim Xiao.
Contained By:	Dissertation Abstracts International68-04B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3259876

Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity.
Qiu, Wei.

Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity. - 159 p.

Adviser: Zhi-Xiong Jim Xiao.

Thesis (Ph.D.)--Boston University, 2007.

The marine double minute (MDM2) protein is a key ubiquitin E3 ligase for p53, and MDM2 activity is regulated by a set of modulators, that include ARF, p300, Yin Yang 1 (YY1) and gankyrin, a newly discovered oncoprotein that is frequently overexpressed in human hepatocarcinomas. We have previously shown that MDM2 binds to and promotes proteasome-dependent degradation of retinoblastoma protein (Rb). Here we show that Rb binds to and inhibits MDM2 E3 ligase activity, resulting in stabilization of p53. In addition, we demonstrate that Rb inhibits MDM2-mediated p53 ubiquitination in a gankyrin-dependent manner and the Rb-gankyrin interaction is critical for Rb-induced p53 stabilization. Furthermore, knockdown of Rb by the retrovirus expressing short hairpin RNA specific for Rb facilitates gankyrin-mediated p53 destabilization, and desensitizes cancer cells to chemotherapy-induced apoptosis. These results reveal a novel regulatory circuit involving p53, MDM2, Rb and gankyrin, and suggest that the status of both p53 and Rb is important for the efficacy of cancer chemotherapy.Subjects--Topical Terms:

1017686
Biology, Cell.

Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity.
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245 1 0 $a Retinoblastoma protein modulates gankyrin-MDM2 in regulation ofp53 protein stability and chemosensitivity.
300 $a 159 p.
500 $a Adviser: Zhi-Xiong Jim Xiao.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2023.
502 $a Thesis (Ph.D.)--Boston University, 2007.
520 $a The marine double minute (MDM2) protein is a key ubiquitin E3 ligase for p53, and MDM2 activity is regulated by a set of modulators, that include ARF, p300, Yin Yang 1 (YY1) and gankyrin, a newly discovered oncoprotein that is frequently overexpressed in human hepatocarcinomas. We have previously shown that MDM2 binds to and promotes proteasome-dependent degradation of retinoblastoma protein (Rb). Here we show that Rb binds to and inhibits MDM2 E3 ligase activity, resulting in stabilization of p53. In addition, we demonstrate that Rb inhibits MDM2-mediated p53 ubiquitination in a gankyrin-dependent manner and the Rb-gankyrin interaction is critical for Rb-induced p53 stabilization. Furthermore, knockdown of Rb by the retrovirus expressing short hairpin RNA specific for Rb facilitates gankyrin-mediated p53 destabilization, and desensitizes cancer cells to chemotherapy-induced apoptosis. These results reveal a novel regulatory circuit involving p53, MDM2, Rb and gankyrin, and suggest that the status of both p53 and Rb is important for the efficacy of cancer chemotherapy.
520 $a In addition, we show that phosphorylation of serine 256 and serine 260 in the acidic domain of MDM2 is critical for MDM2-Rb interaction as well as MDM2 binding to the C8 subunit of the 20S proteasome. Pharmacological inhibition of glycogen synthase kinase 3-beta (GSK3beta) or casein kinase 2 (CK2) results in reduced MDM2-Rb interaction and stabilization of Rb. These data suggest that GSk3beta and CK2 signaling play a role in the MDM2-Rb pathway.
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650 4 $a Biology, Cell. $3 1017686
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773 0 $t Dissertation Abstracts International $g 68-04B.
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