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p53-E2F1 regulatory mechanism of a B...

Knezevic, Dejan.

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p53-E2F1 regulatory mechanism of a Bcl-2 mediated apoptosis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	p53-E2F1 regulatory mechanism of a Bcl-2 mediated apoptosis./
作者:	Knezevic, Dejan.
面頁冊數:	167 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1255.
Contained By:	Dissertation Abstracts International66-03B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3168928
ISBN:	0542049104

p53-E2F1 regulatory mechanism of a Bcl-2 mediated apoptosis.
Knezevic, Dejan.

p53-E2F1 regulatory mechanism of a Bcl-2 mediated apoptosis. - 167 p.

Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1255.

Thesis (Ph.D.)--Yale University, 2005.

Skin cancers are the most prevalent cancers in the United States, comprising as many cases as all other cancers combined. A large majority of non-melanoma skin cancers (basal cell carcinomas and squamous cell carcinomas) carry a mutated P53 tumor suppressor protein. It has been shown that P53 is required for induction of ultraviolet B (UVB) apoptosis in mouse skin cells. We discovered that this defect can be reversed by inactivating another transcription factor, E2f1. I demonstrated that P53 and E2f1 operate in a regulatory feedback loop in which activation of P53 can lead to induction of UVB apoptosis as well as inactivation of E2f1. Activation of E2f1 can lead to upregulation of P53, but also to suppression of an underlying apoptotic pathway.

ISBN: 0542049104Subjects--Topical Terms:

1017686
Biology, Cell.

p53-E2F1 regulatory mechanism of a Bcl-2 mediated apoptosis.
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500 $a Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1255.
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502 $a Thesis (Ph.D.)--Yale University, 2005.
520 $a Skin cancers are the most prevalent cancers in the United States, comprising as many cases as all other cancers combined. A large majority of non-melanoma skin cancers (basal cell carcinomas and squamous cell carcinomas) carry a mutated P53 tumor suppressor protein. It has been shown that P53 is required for induction of ultraviolet B (UVB) apoptosis in mouse skin cells. We discovered that this defect can be reversed by inactivating another transcription factor, E2f1. I demonstrated that P53 and E2f1 operate in a regulatory feedback loop in which activation of P53 can lead to induction of UVB apoptosis as well as inactivation of E2f1. Activation of E2f1 can lead to upregulation of P53, but also to suppression of an underlying apoptotic pathway.
520 $a Immunoblotting of major pro- and anti-apoptotic proteins revealed that non-irradiated E2f1-/- and E2f1-/- x p53-/- (DKO) cells had reduced basal levels of the anti-apoptotic protein Bcl-2 compared to WT and p53-/- counterparts. Overexpression of E2f1 led to the upregulation of basal Bcl-2, and E2F1 RNAi led to the downregulation of Bcl-2, confirming that E2f1 regulates basal levels of Bcl-2. In response to UVB irradiation, Bcl-2 levels declined in WT, but not in apoptosis defective P53-/- cells. The decline was restored in E2f1-/- and DKO fibroblasts. Overexpression of Bcl-2 revealed that the majority (80%) of UVB induced apoptosis is regulated by Bcl-2. Moreover, apoptotic defects seen in P53-/- cells could be reversed by Bcl-2 RNAi treatment.
520 $a The ability of UVB to induce apoptosis and downregulate Bcl-2 in the absence of P53 and E2f1 indicates a second UV-induced pathway converging on Bcl-2. Treatment of cells with JNK RNAi suppressed 40% of apoptosis and prevented early degradation of Bcl-2. Similarly, enhanced repair of DNA damage by photolyase enzyme delayed Bcl-2 degradation and suppressed 40% of apoptosis. However, enhanced repair of DNA damage could not prevent induction of JNK, most likely because JNK induction is much faster (10 minutes) than DNA repair (1--3 hours). DNA damage repair and JNK inactivation were shown to have additive effects on UVB apoptosis, pointing out that these two pathways have some non-overlapping functions.
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