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Studies of TGF-beta/Smad signaling u...

Lim, Sang Kyun.

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Studies of TGF-beta/Smad signaling using peptide aptamers.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Studies of TGF-beta/Smad signaling using peptide aptamers./
作者:	Lim, Sang Kyun.
面頁冊數:	193 p.
附註:	Adviser: F. Michael Hoffmann.
Contained By:	Dissertation Abstracts International68-04B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3261483

Studies of TGF-beta/Smad signaling using peptide aptamers.
Lim, Sang Kyun.

Studies of TGF-beta/Smad signaling using peptide aptamers. - 193 p.

Adviser: F. Michael Hoffmann.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2007.

Smad proteins are intracellular mediators of transforming growth factor beta (TGF-beta) signaling that interact with diverse transcription factors to regulate target gene expression in response to TGF-beta. Lymphoid enhancer factor one (LEF1) is one of the Smad binding proteins. I inserted the Smad interacting motif of LEF1 into a Thioredoxin scaffold (Trx) to generate the peptide aptamer TrxLEF1D which bound to the Smads and inhibited the Smad-LEF1 interaction. TrxLEF1D also impeded the transcriptional activity of the Smad-LEF1 complex but did not affect the transcriptional activity of other Smad complexes tested, indicating that the TrxLef1D peptide aptamer could specifically disrupt a subset of responses mediated by Smads.Subjects--Topical Terms:

1017686
Biology, Cell.

Studies of TGF-beta/Smad signaling using peptide aptamers.
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100 1 $a Lim, Sang Kyun. $3 1267700
245 1 0 $a Studies of TGF-beta/Smad signaling using peptide aptamers.
300 $a 193 p.
500 $a Adviser: F. Michael Hoffmann.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2021.
502 $a Thesis (Ph.D.)--The University of Wisconsin - Madison, 2007.
520 $a Smad proteins are intracellular mediators of transforming growth factor beta (TGF-beta) signaling that interact with diverse transcription factors to regulate target gene expression in response to TGF-beta. Lymphoid enhancer factor one (LEF1) is one of the Smad binding proteins. I inserted the Smad interacting motif of LEF1 into a Thioredoxin scaffold (Trx) to generate the peptide aptamer TrxLEF1D which bound to the Smads and inhibited the Smad-LEF1 interaction. TrxLEF1D also impeded the transcriptional activity of the Smad-LEF1 complex but did not affect the transcriptional activity of other Smad complexes tested, indicating that the TrxLef1D peptide aptamer could specifically disrupt a subset of responses mediated by Smads.
520 $a In an effort to characterize the role of the Smad-LEF1 complex, I established HepG2 cells stably expressing the TrxLEF1D peptide aptamer and used these cells to elucidate a new TGF-beta-independent function of Smad4. Inhibition of Smad4 function by either TrxLEF1D or Smad4 shRNAi reduced c-myc expression and the proliferation rate of HepG2 cells in the absence of TGF-beta signaling. Smad4 bound to a positive regulatory element in the c-myc promoter, stimulating c-myc transcription in the absence of TGF-beta signaling. This new function of Smad4 is in sharp contrast to its TGF-beta-dependent role, which causes the repression of c-myc transcription. Tumor-derived Smad4 mutants retained the TGF-beta-independent function while losing TGF-beta-dependent function. Expression of TrxLEF1D or Smad4 shRNAi reduced the survival of HepG2 cells in low serum.
520 $a TGF-beta induces normal mouse mammary gland (NMuMG) cells to undergo epithelial-to-mesenchymal transition (EMT), and this transition can be blocked by inhibiting Smad signaling with the peptide aptamer TrxSARA. I observed, however, that NMuMG cells expressing TrxSARA undergo EMT when those cells are surrounded by parental NMuMG cells treated with TGF-beta. The effect from the neighboring cells was also demonstrated in co-cultures of NMuMG cells and 4T1 cells, mouse mammary cancer cells. I found that beta-catenin nuclear activity is necessary in the TrxSARA or 4T1 cells for this "neighbor effect". Based on these observations, I propose that cancer cells which have lost responsiveness to TGF-beta, undergo EMT triggered by the mesenchymal transition of neighboring normal epithelial cells responding to TGF-beta.
590 $a School code: 0262.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
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710 2 $a The University of Wisconsin - Madison. $3 626640
773 0 $t Dissertation Abstracts International $g 68-04B.
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791 $a Ph.D.
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