東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

FindBook

Google Book

Amazon

博客來

Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells./
作者:	Flusberg, Deborah.
面頁冊數:	1 online resource (234 pages)
附註:	Source: Dissertations Abstracts International, Volume: 73-08, Section: B.
Contained By:	Dissertations Abstracts International73-08B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3491934click for full text (PQDT)
ISBN:	9781267108197

Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells.
Flusberg, Deborah.

Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells. - 1 online resource (234 pages)

Source: Dissertations Abstracts International, Volume: 73-08, Section: B.

Thesis (Ph.D.)--Harvard University, 2011.

Includes bibliographical references

In response to treatment with TRAIL (TNF-Related Apoptosis Inducing Ligand), individual cells exhibit heterogeneity in cell fate: some cells undergo apoptosis, while others escape death and survive. To understand this divergence in fate, and how it relates to TRAIL sensitivity, we followed the fate of cells which survived an initial treatment with TRAIL at a dose which killed off most of the cell population. Survivor cells were resistant to TRAIL one day following the initial treatment, but regained sensitivity over the course of several days. Resistance was sustained following periodic TRAIL dosings, suggesting a contribution from induced survival signaling. TNF-family ligands ("death ligands") activate both pro-death and pro-survival pathways, but how their dynamics affect the fate of individual cells has not been fully explored. We analyzed survival pathway activation in transiently resistant survivor cells to determine which signals contributed to resistance. Gene expression microarray analysis revealed a distinct gene signature in survivor cells, with more than half of the upregulated genes indicative of an NF-κB-mediated inflammatory response. Biochemical experiments demonstrated that survivor cells were resistant to apoptosis due to attenuated signaling at the Death-Inducing Signaling Complex (DISC), associated with upregulation of the DISC inhibitor protein FLIP. The DISC has previously been implicated as an integrator of life-death decisions in cells treated with death ligands, and DISC-mediated NF-κB activation is presumed to be the major regulator of survival. However, here we show that while inflammatory signaling was dependent on NF-κB, survival and transient resistance were not. Thus, survival and inflammatory signaling in subpopulations of cells were regulated by separate pathways. TRAIL is a potent mediator of apoptosis in cancer cells, but can also lead to context-dependent activation of pro-tumorigenic pathways. Our data support a model in which ligand-induced death and survival signals compete in single cells, modulating both timing of cell death and heterogeneity in response, and leading to the emergence of adaptive states. This scenario puts into question the effectiveness of periodic TRAIL treatments in partially sensitive populations of cancer cells, and suggests that appropriate dosing schedules and co-drugging to target survival pathways are important considerations during TRAIL therapy.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9781267108197Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

ApoptosisIndex Terms--Genre/Form:

542853
Electronic books.

Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells.
LDR:03827nmm a2200385K 4500 001 2358458
005 20230815054813.5
006 m o d
007 cr mn ---uuuuu
008 241011s2011 xx obm 000 0 eng d
020 $a 9781267108197
035 $a (MiAaPQ)AAI3491934
035 $a AAI3491934
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Flusberg, Deborah. $3 3698987
245 1 0 $a Life-Death Signaling and Sensitivity to Death Ligands in Subpopulations of Cells.
264 0 $c 2011
300 $a 1 online resource (234 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 73-08, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Sorger, Peter.
502 $a Thesis (Ph.D.)--Harvard University, 2011.
504 $a Includes bibliographical references
520 $a In response to treatment with TRAIL (TNF-Related Apoptosis Inducing Ligand), individual cells exhibit heterogeneity in cell fate: some cells undergo apoptosis, while others escape death and survive. To understand this divergence in fate, and how it relates to TRAIL sensitivity, we followed the fate of cells which survived an initial treatment with TRAIL at a dose which killed off most of the cell population. Survivor cells were resistant to TRAIL one day following the initial treatment, but regained sensitivity over the course of several days. Resistance was sustained following periodic TRAIL dosings, suggesting a contribution from induced survival signaling. TNF-family ligands ("death ligands") activate both pro-death and pro-survival pathways, but how their dynamics affect the fate of individual cells has not been fully explored. We analyzed survival pathway activation in transiently resistant survivor cells to determine which signals contributed to resistance. Gene expression microarray analysis revealed a distinct gene signature in survivor cells, with more than half of the upregulated genes indicative of an NF-κB-mediated inflammatory response. Biochemical experiments demonstrated that survivor cells were resistant to apoptosis due to attenuated signaling at the Death-Inducing Signaling Complex (DISC), associated with upregulation of the DISC inhibitor protein FLIP. The DISC has previously been implicated as an integrator of life-death decisions in cells treated with death ligands, and DISC-mediated NF-κB activation is presumed to be the major regulator of survival. However, here we show that while inflammatory signaling was dependent on NF-κB, survival and transient resistance were not. Thus, survival and inflammatory signaling in subpopulations of cells were regulated by separate pathways. TRAIL is a potent mediator of apoptosis in cancer cells, but can also lead to context-dependent activation of pro-tumorigenic pathways. Our data support a model in which ligand-induced death and survival signals compete in single cells, modulating both timing of cell death and heterogeneity in response, and leading to the emergence of adaptive states. This scenario puts into question the effectiveness of periodic TRAIL treatments in partially sensitive populations of cancer cells, and suggests that appropriate dosing schedules and co-drugging to target survival pathways are important considerations during TRAIL therapy.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Cellular biology. $3 3172791
653 $a Apoptosis
653 $a Cell death
653 $a Death ligands
653 $a Life-death signaling
653 $a Subpopulations
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0379
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Harvard University. $3 528741
773 0 $t Dissertations Abstracts International $g 73-08B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3491934 $z click for full text (PQDT)