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Proteasomal regulation of CCAAT/enha...

Shim, Minsub.

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Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas./
作者:	Shim, Minsub.
面頁冊數:	179 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1831.
Contained By:	Dissertation Abstracts International65-04B.
標題:	Health Sciences, Toxicology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128791
ISBN:	049676053X

Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas.
Shim, Minsub.

Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas. - 179 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1831.

Thesis (Ph.D.)--North Carolina State University, 2003.

The CCAAT/enhancer binding proteins (C/EBPs) are members of the basic leucine zipper (bZIP) class of transcription factors. C/EBPalpha is involved in mitotic growth arrest/differentiation and has been implicated as a human tumor suppressor in acute myeloid leukemia. C/EBPalpha is abundantly expressed in mouse keratinocytes. The purpose of this study was to examine the regulation of the C/EBPalpha protein and to determine if C/EBPalpha expression/function is altered in skin squamous cell carcinomas.

ISBN: 049676053XSubjects--Topical Terms:

1017752
Health Sciences, Toxicology.

Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas.
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245 1 0 $a Proteasomal regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha) and diminished expression of C/EBPalpha in squamous cell carcinomas.
300 $a 179 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1831.
500 $a Adviser: Robert C. Smart.
502 $a Thesis (Ph.D.)--North Carolina State University, 2003.
520 $a The CCAAT/enhancer binding proteins (C/EBPs) are members of the basic leucine zipper (bZIP) class of transcription factors. C/EBPalpha is involved in mitotic growth arrest/differentiation and has been implicated as a human tumor suppressor in acute myeloid leukemia. C/EBPalpha is abundantly expressed in mouse keratinocytes. The purpose of this study was to examine the regulation of the C/EBPalpha protein and to determine if C/EBPalpha expression/function is altered in skin squamous cell carcinomas.
520 $a We found that C/EBPalpha is a short-lived protein with a half-life of &sim;1 hour and treatment with proteasome inhibitors blocked the degradation of C/EBPalpha protein. Poly-ubiquitinated C/EBPalpha were detected in BALB/MK2 and C/EBPalpha was degraded by the proteasome in an ATP- and ubiquitin-dependent manner.{09}GSK3 is a known C/EBPalpha kinase and treatment of keratinocytes with LiCl, an inhibitor of GSK3 resulted in; (i) an increase in C/EBPalpha protein levels, (ii) increased electrophoretic mobility of C/EBPalpha protein and (iii) no increase in C/EBPalpha mRNA levels suggesting that GSK3-mediated phosphorylation of C/EBPalpha may target it for proteasomal degradation. However, a mutant C/EBPalpha containing mutations in the GSK3 phosphorylation sites (T222A and T226A) retained its response to LiCl and additional pharmacological inhibitors of GSK3 did not alter C/EBPalpha levels indicating the effects of LiCl on C/EBPalpha are GSK3-independent.{09}LiCl treatment inhibited C/EBPalpha degradation and produced a six-fold increase in the half-life of C/EBPalpha protein.{09}In vitro studies revealed that LiCl inhibited proteasomal degradation of C/EBPalpha. These results demonstrate C/EBPalpha is degraded via a proteasomal pathway and LiCl stabilizes C/EBPalpha through a GSK3 independent pathway involving inhibition of proteasome activity.
520 $a The expression of C/EBPalpha was evaluated in mouse skin SCC lines. C/EBPalpha mRNA and protein levels were greatly diminished or undetectable in all seven SCC cell lines compared to normal keratinocytes.{09}Forced expression of C/EBPalpha resulted in the inhibition in SCC cell proliferation. Expression of C/EBPalpha also resulted in the expression of loricrin, a late stage marker of squamous differentiation. Treatment with 5'-aza-deoxycytidine increased C/EBPalpha expression in some SCC cell lines suggesting the C/EBPalpha promoter region may be transcriptionally silenced by hypermethylation. C/EBPalpha expression was negligible in all 14/14 SCC examined compared to normal epidermis. These results suggest the loss of C/EBPalpha expression may contribute to the altered growth and differentiation characteristics of skin SCCs.
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650 4 $a Health Sciences, Toxicology. $3 1017752
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