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Functional analysis ofp53 phosphoryl...

Bean, Lora Jeannette Hughes.

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Functional analysis ofp53 phosphorylation.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Functional analysis ofp53 phosphorylation./
作者:	Bean, Lora Jeannette Hughes.
面頁冊數:	173 p.
附註:	Adviser: George R. Stark.
Contained By:	Dissertation Abstracts International63-07B.
標題:	Biology, Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3058829
ISBN:	0493744738

Functional analysis ofp53 phosphorylation.
Bean, Lora Jeannette Hughes.

Functional analysis ofp53 phosphorylation. - 173 p.

Adviser: George R. Stark.

Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2002.

Changes in the phosphorylation state of p53 are important in increasing its half-life and potency as a transcription factor. To investigate their roles, serine residues 15, 20, and 37 and threonine residue 18 were mutated to alanine and the mutated proteins were expressed stably at low basal levels in Li-Fraumeni-derived and HT1080-derived p53-null human fibroblasts. Mutation of serine 20 completely destabilized p53 and, therefore, the protein could not be expressed at a significant level. The accumulation of p53 after DNA damage was analyzed quantitatively in multiple clones. In the Li-Fraumeni background, mutation of serine 15 and serine 37, separately or together, threonine 18 impaired the accumulation of p53 protein after exposing the cells to ultraviolet radiation (50–100% increase for the mutant proteins, 500% increase for wild-type p53) but not after treatment with adriamycin. In the HT1080 background, mutation of threonine 18 impaired the accumulation of the protein after both ultraviolet radiation and adriamycin treatment. These experiments demonstrated that ultraviolet radiation and adriamycin-induced damage signal to p53 through separate pathways. Analysis of p53-dependent transcription revealed that the phosphorylation of serine 15 is required to maintain basal levels of p21 mRNA and that the phosphorylation of threonine 18 is required for p53-dpendent transactivation after ultraviolet irradiation. These results provide new evidence for important functions of threonine 18 and serine 37 phosphorylation, clearly distinguish the pathways of p53 activation in response to ultraviolet radiation or DNA damage inflicted by adriamycin, and reveal that serine 15 is crucial to support the p53-mediated basal expression of p21.

ISBN: 0493744738Subjects--Topical Terms:

1017730
Biology, Genetics.

Functional analysis ofp53 phosphorylation.
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520 $a Changes in the phosphorylation state of p53 are important in increasing its half-life and potency as a transcription factor. To investigate their roles, serine residues 15, 20, and 37 and threonine residue 18 were mutated to alanine and the mutated proteins were expressed stably at low basal levels in Li-Fraumeni-derived and HT1080-derived p53-null human fibroblasts. Mutation of serine 20 completely destabilized p53 and, therefore, the protein could not be expressed at a significant level. The accumulation of p53 after DNA damage was analyzed quantitatively in multiple clones. In the Li-Fraumeni background, mutation of serine 15 and serine 37, separately or together, threonine 18 impaired the accumulation of p53 protein after exposing the cells to ultraviolet radiation (50–100% increase for the mutant proteins, 500% increase for wild-type p53) but not after treatment with adriamycin. In the HT1080 background, mutation of threonine 18 impaired the accumulation of the protein after both ultraviolet radiation and adriamycin treatment. These experiments demonstrated that ultraviolet radiation and adriamycin-induced damage signal to p53 through separate pathways. Analysis of p53-dependent transcription revealed that the phosphorylation of serine 15 is required to maintain basal levels of p21 mRNA and that the phosphorylation of threonine 18 is required for p53-dpendent transactivation after ultraviolet irradiation. These results provide new evidence for important functions of threonine 18 and serine 37 phosphorylation, clearly distinguish the pathways of p53 activation in response to ultraviolet radiation or DNA damage inflicted by adriamycin, and reveal that serine 15 is crucial to support the p53-mediated basal expression of p21.
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