schliessen

Filtern

 

Bibliotheken

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations ma... Full description

Journal Title: Environmental Health Perspectives (Online) Dec 2014, Vol.122(12), p.1261
Main Author: Zhang, Qiang
Other Authors: Bhattacharya, Sudin , Conolly, Rory , Clewell, Harvey , Kaminski, Norbert , Andersen, Melvin
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 15529924 ; DOI: 10.1289/ehp.1408244
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: proquest1661372965
title: Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
format: Article
creator:
  • Zhang, Qiang
  • Bhattacharya, Sudin
  • Conolly, Rory
  • Clewell, Harvey
  • Kaminski, Norbert
  • Andersen, Melvin
subjects:
  • Health Risk Assessment
  • Biology
  • Chemicals
  • Studies
  • Population
  • Homeostasis
  • Toxicology
ispartof: Environmental Health Perspectives (Online), Dec 2014, Vol.122(12), p.1261
description: Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
language: eng
source:
identifier: E-ISSN: 15529924 ; DOI: 10.1289/ehp.1408244
fulltext: fulltext_linktorsrc
issn:
  • 15529924
  • 1552-9924
url: Link


@attributes
ID288748991
RANK0.07
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
LOCALfalse
PrimoNMBib
record
control
sourcerecordid1661372965
sourceidproquest
recordidTN_proquest1661372965
sourcesystemOther
pqid1661372965
galeid398253362
display
typearticle
titleMolecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
creatorZhang, Qiang ; Bhattacharya, Sudin ; Conolly, Rory ; Clewell, Harvey ; Kaminski, Norbert ; Andersen, Melvin
ispartofEnvironmental Health Perspectives (Online), Dec 2014, Vol.122(12), p.1261
identifierE-ISSN: 15529924 ; DOI: 10.1289/ehp.1408244
subjectHealth Risk Assessment ; Biology ; Chemicals ; Studies ; Population ; Homeostasis ; Toxicology
descriptionBackground: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
languageeng
source
version8
oafree_for_read
lds50peer_reviewed
links
openurl$$Topenurl_article
openurlfulltext$$Topenurlfull_article
linktorsrc$$Uhttp://search.proquest.com/docview/1661372965/?pq-origsite=primo$$EView_record_in_ProQuest_(subscribers_only)
search
creatorcontrib
0Zhang, Qiang
1Bhattacharya, Sudin
2Conolly, Rory
3Clewell, Harvey
4Kaminski, Norbert
5Andersen, Melvin
titleMolecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
descriptionBackground: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
subject
0Health Risk Assessment
1Biology
2Chemicals
3Studies
4Population
5Homeostasis
6Toxicology
general
0English
1National Institute of Environmental Health Sciences
210.1289/ehp.1408244
3ABI/INFORM Global
4Medical Database
5Consumer Health Database
6Health & Medical Collection (Alumni edition)
7Medical Database (Alumni edition)
8Nursing & Allied Health Database (Alumni edition)
9ProQuest Pharma Collection
10Health & Medical Collection
11Nursing & Allied Health Database
12ABI/INFORM Global (Alumni edition)
13ProQuest Public Health
14Engineering Database
15Consumer Health Database (Alumni edition)
16Publicly Available Content Database
17Research Library China
18ABI/INFORM Collection China
19Environmental Science Database (ProQuest)
20ABI/INFORM Complete
21Engineering Research Database
22Technology Research Database
23ProQuest Nursing & Allied Health Source
24ProQuest Research Library
25Environment Abstracts
26ProQuest Biological Science Collection
27ProQuest Central
28ProQuest Engineering Collection
29ProQuest Environmental Science Collection
30ProQuest Hospital Collection
31ProQuest Natural Science Collection
32ProQuest Technology Collection
33Research Library (Alumni edition)
34ABI/INFORM Collection (Alumni edition)
35Hospital Premium Collection (Alumni edition)
36ProQuest SciTech Collection
37ProQuest Health & Medical Complete
38ProQuest Medical Library
39ProQuest Business Collection
40British Nursing Index with Full Text
41Agricultural & Environmental Science Database
42Biological Science Database
43Business Premium Collection
44Business Premium Collection (Alumni edition)
45Materials Science & Engineering Database
46Natural Science Collection
47ProQuest Central (new)
48ProQuest Central K-12
49ProQuest Central Korea
50Research Library Prep
51SciTech Premium Collection
52Technology Collection
53Health Research Premium Collection
54Health Research Premium Collection (Alumni edition)
55ProQuest Central Essentials
56ProQuest Central China
57ProQuest One Academic
58Environmental Science Index (ProQuest)
59Biological Science Index (ProQuest)
60Environmental Science Collection (ProQuest)
61Engineering Collection (ProQuest)
sourceidproquest
recordidproquest1661372965
issn
015529924
11552-9924
rsrctypearticle
creationdate2014
addtitleEnvironmental Health Perspectives (Online)
searchscope
01000001
11000273
21006072
31006454
41006520
51006759
61006761
71006762
81006763
91006815
101006993
111007067
121007107
131007289
141007488
151007530
161007617
171007853
181007899
191007902
201007918
211007945
221008005
231008008
241008165
251008167
261008174
271008510
281008685
291008886
301009127
311009240
321009384
331009385
341009714
3510000004
3610000005
3710000006
3810000008
3910000013
4010000015
4110000020
4210000022
4310000025
4410000029
4510000034
4610000038
4710000039
4810000041
4910000043
5010000047
5110000050
5210000053
5310000064
5410000068
5510000117
5610000118
5710000119
5810000120
5910000155
6010000156
6110000157
6210000158
6310000164
6410000181
6510000182
6610000186
6710000194
6810000198
6910000200
7010000209
7110000217
7210000234
7310000238
7410000241
7510000242
7610000250
7710000253
7810000255
7910000256
8010000257
8110000258
8210000259
8310000260
8410000265
8510000268
8610000270
8710000271
8810000281
8910000300
9010000302
9110000348
9210000349
9310000350
9410000354
9510000356
9610000360
97proquest
scope
01000001
11000273
21006072
31006454
41006520
51006759
61006761
71006762
81006763
91006815
101006993
111007067
121007107
131007289
141007488
151007530
161007617
171007853
181007899
191007902
201007918
211007945
221008005
231008008
241008165
251008167
261008174
271008510
281008685
291008886
301009127
311009240
321009384
331009385
341009714
3510000004
3610000005
3710000006
3810000008
3910000013
4010000015
4110000020
4210000022
4310000025
4410000029
4510000034
4610000038
4710000039
4810000041
4910000043
5010000047
5110000050
5210000053
5310000064
5410000068
5510000117
5610000118
5710000119
5810000120
5910000155
6010000156
6110000157
6210000158
6310000164
6410000181
6510000182
6610000186
6710000194
6810000198
6910000200
7010000209
7110000217
7210000234
7310000238
7410000241
7510000242
7610000250
7710000253
7810000255
7910000256
8010000257
8110000258
8210000259
8310000260
8410000265
8510000268
8610000270
8710000271
8810000281
8910000300
9010000302
9110000348
9210000349
9310000350
9410000354
9510000356
9610000360
97proquest
lsr43
01000001true
11000273true
21006072true
31006454true
41006520true
51006759true
61006761true
71006762true
81006763true
91006815true
101006993true
111007067true
121007107true
131007289true
141007488false
151007530false
161007617true
171007853true
181007899true
191007902true
201007918false
211007945true
221008005true
231008008true
241008165true
251008167true
261008174true
271008510true
281008685true
291008886true
301009127true
311009240true
321009384true
331009385true
341009714true
3510000004false
3610000005false
3710000006false
3810000008true
3910000013false
4010000015false
4110000020true
4210000022true
4310000025true
4410000029false
4510000034true
4610000038false
4710000039true
4810000041true
4910000043true
5010000047true
5110000050true
5210000053true
5310000064true
5410000068true
5510000117true
5610000118true
5710000119true
5810000120true
5910000155true
6010000156true
6110000157true
6210000158true
6310000164true
6410000181true
6510000182true
6610000186true
6710000194true
6810000198false
6910000200false
7010000209false
7110000217false
7210000234true
7310000238false
7410000241true
7510000242true
7610000250true
7710000253true
7810000255true
7910000256true
8010000257true
8110000258true
8210000259true
8310000260true
8410000265true
8510000268true
8610000270true
8710000271true
8810000281true
8910000300true
9010000302true
9110000348true
9210000349false
9310000350false
9410000354true
9510000356true
9610000360true
startdate20141201
enddate20141201
citationpf 1261 vol 122 issue 12
lsr30VSR-Enriched:[galeid, pages, issn, pqid]
sort
titleMolecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
authorZhang, Qiang ; Bhattacharya, Sudin ; Conolly, Rory ; Clewell, Harvey ; Kaminski, Norbert ; Andersen, Melvin
creationdate20141201
lso0120141201
facets
frbrgroupid-3890985361432232489
frbrtype5
languageeng
creationdate2014
topic
0Health Risk Assessment
1Biology
2Chemicals
3Studies
4Population
5Homeostasis
6Toxicology
collection
0ABI/INFORM Global
1Medical Database
2Consumer Health Database
3Health & Medical Collection (Alumni edition)
4Medical Database (Alumni edition)
5Nursing & Allied Health Database (Alumni edition)
6ProQuest Pharma Collection
7Health & Medical Collection
8Nursing & Allied Health Database
9ABI/INFORM Global (Alumni edition)
10ProQuest Public Health
11Engineering Database
12Consumer Health Database (Alumni edition)
13Publicly Available Content Database
14Research Library China
15ABI/INFORM Collection China
16Environmental Science Database (ProQuest)
17ABI/INFORM Complete
18Engineering Research Database
19Technology Research Database
20ProQuest Nursing & Allied Health Source
21ProQuest Research Library
22Environment Abstracts
23ProQuest Biological Science Collection
24ProQuest Central
25ProQuest Engineering Collection
26ProQuest Environmental Science Collection
27ProQuest Hospital Collection
28ProQuest Natural Science Collection
29ProQuest Technology Collection
30Research Library (Alumni edition)
31ABI/INFORM Collection (Alumni edition)
32Hospital Premium Collection (Alumni edition)
33ProQuest SciTech Collection
34ProQuest Health & Medical Complete
35ProQuest Medical Library
36ProQuest Business Collection
37British Nursing Index with Full Text
38Agricultural & Environmental Science Database
39Biological Science Database
40Business Premium Collection
41Business Premium Collection (Alumni edition)
42Materials Science & Engineering Database
43Natural Science Collection
44ProQuest Central (new)
45ProQuest Central K-12
46ProQuest Central Korea
47Research Library Prep
48SciTech Premium Collection
49Technology Collection
50Health Research Premium Collection
51Health Research Premium Collection (Alumni edition)
52ProQuest Central Essentials
53ProQuest Central China
54ProQuest One Academic
55Environmental Science Index (ProQuest)
56Biological Science Index (ProQuest)
57Environmental Science Collection (ProQuest)
58Engineering Collection (ProQuest)
prefilterarticles
rsrctypearticles
creatorcontrib
0Zhang, Qiang
1Bhattacharya, Sudin
2Conolly, Rory
3Clewell, Harvey
4Kaminski, Norbert
5Andersen, Melvin
jtitleEnvironmental Health Perspectives (Online)
toplevelpeer_reviewed
delivery
delcategoryRemote Search Resource
fulltextfulltext_linktorsrc
addata
aulast
0Zhang
1Bhattacharya
2Conolly
3Clewell
4Kaminski
5Andersen
aufirst
0Qiang
1Sudin
2Rory
3Harvey
4Norbert
5Melvin
au
0Zhang, Qiang
1Bhattacharya, Sudin
2Conolly, Rory
3Clewell, Harvey
4Kaminski, Norbert
5Andersen, Melvin
atitleMolecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
jtitleEnvironmental Health Perspectives (Online)
risdate20141201
volume122
issue12
spage1261
eissn15529924
formatjournal
genrearticle
ristypeJOUR
abstractBackground: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
copResearch Triangle Park
pubNational Institute of Environmental Health Sciences
doi10.1289/ehp.1408244
urlhttp://search.proquest.com/docview/1661372965/
pages1261-1270
issn00916765
oafree_for_read
date2014-12-01