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The mechanism of the transcription a...

Hong Kong University of Science and Technology (Hong Kong)., HKUST.

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The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain./
Author:	Ng, King Pan.
Description:	136 p.
Notes:	Adviser: Kevin A. W. Lee.
Contained By:	Dissertation Abstracts International69-10B.
Subject:	Biology, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3330959
ISBN:	9780549879695

The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain.
Ng, King Pan.

The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain. - 136 p.

Adviser: Kevin A. W. Lee.

Thesis (Ph.D.)--Hong Kong University of Science and Technology (Hong Kong), 2008.

Chromosomal fusion of Ewings Sarcoma gene (EWS) to various transcription factors produces a family of oncogenic EWS-Fusion-Proteins (EFPs) that cause distinct human cancers, dictated by the DNA-binding domain of the EWS fusion partner. EFPs are also involved in tumor maintenance showing that they are therapeutic targets. EFPs function as potent transcriptional activators dependent on the EWS Activation Domain (EAD), and thus transcriptional deregulation is thought to be critical for all EFP-induced tumors.

ISBN: 9780549879695Subjects--Topical Terms:

1018625
Biology, General.

The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain.
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020 $a 9780549879695
035 $a (UMI)AAI3330959
035 $a AAI3330959
040 $a UMI $c UMI
100 1 $a Ng, King Pan. $3 1023363
245 1 4 $a The mechanism of the transcription activation mediated by the Ewing Sarcoma activation domain.
300 $a 136 p.
500 $a Adviser: Kevin A. W. Lee.
500 $a Source: Dissertation Abstracts International, Volume: 69-10, Section: B, page: 5852.
502 $a Thesis (Ph.D.)--Hong Kong University of Science and Technology (Hong Kong), 2008.
520 $a Chromosomal fusion of Ewings Sarcoma gene (EWS) to various transcription factors produces a family of oncogenic EWS-Fusion-Proteins (EFPs) that cause distinct human cancers, dictated by the DNA-binding domain of the EWS fusion partner. EFPs are also involved in tumor maintenance showing that they are therapeutic targets. EFPs function as potent transcriptional activators dependent on the EWS Activation Domain (EAD), and thus transcriptional deregulation is thought to be critical for all EFP-induced tumors.
520 $a The overall aims of this thesis were to characterize the molecular mechanism of EAD-mediated trans-activation and several barriers had to be overcome. First, the EAD is extended (&sim;260 residues) and consists mostly of 31 copies of a Degenerate Hexapeptide Repeat (DHRs, consensus SYGQQS with conserved Tyr) which greatly hinders functional analysis. Second, the biased amino acid composition of EAD is characteristic of Intrinsically Disordered proteins (IDPs) that are not amenable to classical structural analysis and extended repetitive IDPS (such the EAD) are particularly problematic. Third, a manipulatable in vitro transcription assay for the EAD had not been established.
520 $a By exploiting the recent advance of total gene synthesis I was able to systematically mutagenized the EAD and determine the effect on trans-activation by EWS/ATF1. I made several notable findings. First, multiple Tyr residues are specifically required. Second, an EAD in which every Tyr is replaced by Phe retains activity, establishing that an aromatic side chain is sufficient. Third and quite remarkably, sequence composition (and not the DHR) confers EAD activity. Thus the EAD appears to be a highly extended and malleable structure with several critical Tyr residues. To complement the above functional analysis I employed a sensitive computational Predictor of Natural Disordered Regions (PONDR VL3) to directly assess the EAD. POND VL3 analysis demonstrated a robust correlation between EAD down-mutations and disorder propensity, indicating that the EAD contains multiple/complex Tyr-dependent Molecular Recognition Features.
520 $a To enable study of the mechanism of EAD action I attempted to establish an EAD-dependent transcription assay using soluble nuclear extracts from mammalian cells and exogenous EAD-containing activators. While minimal activators (previously characterized in vivo) exhibited activity in vitro, this activity was, surprisingly, not dependent on the Tyr residues critical for in vivo function. Based on several considerations I therefore suggest that the cellular context (for example the presence of chromatin) may be required for EAD-mediated transcriptional activation.
520 $a To conclude, my study exemplified the first detailed structural analysis of an extended and repetitive IDP (the EAD). I also speculate from my data and other published findings, that the length and malleability of the EAD allows promiscuous interactions with multiple different proteins resulting in potent transcriptional activation. Future progress will depend on identification of cognate EAD-binding proteins and the EAD mutants characterized here should prove invaluable for this task.
590 $a School code: 1223.
650 4 $a Biology, General. $3 1018625
690 $a 0306
710 2 $a Hong Kong University of Science and Technology (Hong Kong). $b HKUST. $3 1020712
773 0 $t Dissertation Abstracts International $g 69-10B.
790 $a 1223
790 1 0 $a Lee, Kevin A. W., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3330959