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Modification of the alternative spli...

Mercatante, Danielle Rene.

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Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells./
Author:	Mercatante, Danielle Rene.
Description:	244 p.
Notes:	Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5174.
Contained By:	Dissertation Abstracts International63-11B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3070883
ISBN:	0493906851

Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells.
Mercatante, Danielle Rene.

Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells. - 244 p.

Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5174.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2002.

Bcl-x pre-mRNA is alternatively spliced to yield two products with opposing functions. The use of the upstream alternative 5' splice site in exon II of Bcl-x pre-mRNA results in Bcl-xS; the translated protein of Bcl-xS has pro-apoptotic functions. Use of the downstream alternative 5 ' splice site in exon II of Bcl-x pre-mRNA results in Bcl-xL; the translated protein of Bcl-xL has anti-apoptotic functions. Cancer cells often have altered apoptotic pathways, giving the cells resistance to conventional anti-neoplastic treatments. Various cancers overexpress Bcl-xL, an anti-apoptotic member of the Bcl-2 family of apoptotic proteins. The increased levels of Bcl-xL negatively correlate with sensitivity of cancers to several chemotherapeutic agents.

ISBN: 0493906851Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells.
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100 1 $a Mercatante, Danielle Rene. $3 1900802
245 1 0 $a Modification of the alternative splicing patterns of Bcl-x pre-mRNA: Induction of cell death and chemosensitization of cancer cells.
300 $a 244 p.
500 $a Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5174.
500 $a Director: Ryszard Kole.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2002.
520 $a Bcl-x pre-mRNA is alternatively spliced to yield two products with opposing functions. The use of the upstream alternative 5' splice site in exon II of Bcl-x pre-mRNA results in Bcl-xS; the translated protein of Bcl-xS has pro-apoptotic functions. Use of the downstream alternative 5 ' splice site in exon II of Bcl-x pre-mRNA results in Bcl-xL; the translated protein of Bcl-xL has anti-apoptotic functions. Cancer cells often have altered apoptotic pathways, giving the cells resistance to conventional anti-neoplastic treatments. Various cancers overexpress Bcl-xL, an anti-apoptotic member of the Bcl-2 family of apoptotic proteins. The increased levels of Bcl-xL negatively correlate with sensitivity of cancers to several chemotherapeutic agents.
520 $a Research has shown that antisense oligonucleotides targeted to aberrant splice sites of thalassemic beta-globin pre-mRNA can redirect the splicing machinery to utilize correct splice sites. Therefore, an antisense oligonucleotide was designed towards the downstream alternative 5' splice site of Bcl-x pre-mRNA. This was hypothesized to shift the splicing pattern of Bcl-x pre-mRNA from Bcl-xL to Bcl-xS, induce cell death, and sensitize cancer cells to chemotherapeutic agents and radiation.
520 $a Results in this dissertation showed that an antisense oligonucleotide (5'Bcl-x AS) targeted to the downstream alternative 5 ' splice site of Bcl-x pre-mRNA shifted the splicing pattern of Bcl-x pre-mRNA from the anti-apoptotic variant, Bcl-xL, to the pro-apoptotic variant, Bcl-xS (Chapter 3). This shift in splicing induced cell death in cancer cell lines (Chapter 4). In order to be a useful therapy, cancers that may benefit the most from such treatment must be identified. In addition, it is important to determine what combination of drugs may provide enhanced effects. I have given evidence that 5'Bcl-x AS induced cell death to a greater extent in cells expressing higher levels of Bcl-xL (Chapter 5). Regardless of the endogenous Bcl-xL levels, 5'Bcl-x AS sensitized both PC-3 (prostate cancer) and MCF-7 (breast cancer) cell lines to various chemotherapeutic agents and radiation (chapter 6). These results suggested a specificity of 5'Bcl-x AS treatment for cancer cells, many of which express higher levels of Bcl-xL compared with normal cells. In addition, the results demonstrated the potential combinatorial use of 5'Bcl-x AS with various anti-cancer therapies for the treatment of cancers.
590 $a School code: 0153.
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Biology, Cell. $3 1017686
690 $a 0419
690 $a 0992
690 $a 0379
710 2 0 $a The University of North Carolina at Chapel Hill. $3 1017449
773 0 $t Dissertation Abstracts International $g 63-11B.
790 1 0 $a Kole, Ryszard, $e advisor
790 $a 0153
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3070883