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Induction of the small heat shock pr...

Evans, Joseph Robert.

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Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha./
作者:	Evans, Joseph Robert.
面頁冊數:	175 p.
附註:	Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7362.
Contained By:	Dissertation Abstracts International70-12B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3386529
ISBN:	9781109518764

Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha.
Evans, Joseph Robert.

Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha. - 175 p.

Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7362.

Thesis (Ph.D.)--Northwestern University, 2009.

The small heat shock protein alphaB-crystallin is induced by multiple cellular stressors and confers a cytoprotective effect by suppressing aggregation of denatured proteins, inhibiting apoptosis and acting as an antioxidant. alphaB-Crystallin is constitutively expressed in several aggressive tumor types, including breast cancer, malignant gliomas, and head and neck carcinomas. I sought to investigate the mechanisms of deregulated alphaB-crystallin expression in tumor cells. A bioinformatics search of the proximal promoter of alphaB-crystallin for DNA binding motifs identified a putative response element (RE) for the p53 tumor suppressor protein. Gene reporter assays demonstrated that wild-type p53 transactivates the alphaB-crystallin promoter, and this transactivation is abrogated by mutation of the putative p53RE. I also observed that ectopic expression of wild-type p53, but not a DNA binding mutant, increases alphaB-crystallin mRNA and protein levels. Additionally, silencing p53 abrogated alphaB-crystallin induction by genotoxic stress. However, the induction of alphaB-crystallin by p53 is delayed compared to that of the well-characterized p53 target gene CDKN1A (p21), and chromatin immunoprecipitation (ChIP) failed to demonstrate p53 binding to the alphaB-crystallin promoter. These results led me to hypothesize that p53 might be acting indirectly or in conjunction with a p53 family member (p63 or p73), which also bind to p53REs to regulate gene expression. Consistent with this idea, the DeltaNp73 isoform is dramatically induced by p53 and silencing p73 suppresses the transcriptional activation of alphaB-crystallin following p53 expression. Moreover, ectopic expression of the DeltaNp73alpha isoform (but not other p73 isoforms) increased alphaB-crystallin mRNA levels. My data strongly suggest that p53 induces DeltaNp73alpha, which in turn transactivates alphaB-crystallin in a novel fashion. This mechanism may have important therapeutic implications because DeltaNp73 is commonly co-expressed with wild-type p53 in breast and other cancers and inhibits p53-dependent apoptosis. Collectively, my results link the molecular chaperone alphaB-crystallin to the cellular response to genotoxic stress via a novel mechanism of transcriptional regulation by p53 and DeltaNp73alpha.

ISBN: 9781109518764Subjects--Topical Terms:

1017719
Biology, Molecular.

Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha.
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245 1 0 $a Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and DeltaNp73alpha.
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500 $a Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7362.
500 $a Adviser: Vincent L. Cryns.
502 $a Thesis (Ph.D.)--Northwestern University, 2009.
520 $a The small heat shock protein alphaB-crystallin is induced by multiple cellular stressors and confers a cytoprotective effect by suppressing aggregation of denatured proteins, inhibiting apoptosis and acting as an antioxidant. alphaB-Crystallin is constitutively expressed in several aggressive tumor types, including breast cancer, malignant gliomas, and head and neck carcinomas. I sought to investigate the mechanisms of deregulated alphaB-crystallin expression in tumor cells. A bioinformatics search of the proximal promoter of alphaB-crystallin for DNA binding motifs identified a putative response element (RE) for the p53 tumor suppressor protein. Gene reporter assays demonstrated that wild-type p53 transactivates the alphaB-crystallin promoter, and this transactivation is abrogated by mutation of the putative p53RE. I also observed that ectopic expression of wild-type p53, but not a DNA binding mutant, increases alphaB-crystallin mRNA and protein levels. Additionally, silencing p53 abrogated alphaB-crystallin induction by genotoxic stress. However, the induction of alphaB-crystallin by p53 is delayed compared to that of the well-characterized p53 target gene CDKN1A (p21), and chromatin immunoprecipitation (ChIP) failed to demonstrate p53 binding to the alphaB-crystallin promoter. These results led me to hypothesize that p53 might be acting indirectly or in conjunction with a p53 family member (p63 or p73), which also bind to p53REs to regulate gene expression. Consistent with this idea, the DeltaNp73 isoform is dramatically induced by p53 and silencing p73 suppresses the transcriptional activation of alphaB-crystallin following p53 expression. Moreover, ectopic expression of the DeltaNp73alpha isoform (but not other p73 isoforms) increased alphaB-crystallin mRNA levels. My data strongly suggest that p53 induces DeltaNp73alpha, which in turn transactivates alphaB-crystallin in a novel fashion. This mechanism may have important therapeutic implications because DeltaNp73 is commonly co-expressed with wild-type p53 in breast and other cancers and inhibits p53-dependent apoptosis. Collectively, my results link the molecular chaperone alphaB-crystallin to the cellular response to genotoxic stress via a novel mechanism of transcriptional regulation by p53 and DeltaNp73alpha.
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