Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells
Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells.
Vyšlo v časopise:
Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells. PLoS Pathog 6(9): e32767. doi:10.1371/journal.ppat.1001103
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1001103
Souhrn
Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells.
Zdroje
1. DabrowskaA
KimN
AldoviniA
2008
Tat-Induced Foxo3a Is A Key Mediator Of Apoptosis In Hiv-1-Infected Human Cd4+ T Lymphocytes.
J Immunol
181
8460
8477
2. ModurV
NagarajanR
EversBm
MilbrandtJ
2002
Foxo Proteins Regulate Tumor Necrosis Factor-Related Apoptosis Inducing Ligand Expression. Implications For Pten Mutation In Prostate Cancer.
J Biol Chem
277
47928
47937
3. SuntersA
Fernandez De MattosS
StahlM
BrosensJj
ZoumpoulidouG
2003
Foxo3a Transcriptional Regulation Of Bim Controls Apoptosis In Paclitaxel-Treated Breast Cancer Cell Lines.
J Biol Chem
278
49795
49805
4. BaronV
AdamsonEd
CalogeroA
RagonaG
MercolaD
2006
The Transcription Factor Egr1 Is A Direct Regulator Of Multiple Tumor Suppressors Including Tgfbeta1, Pten, P53, And Fibronectin.
Cancer Gene Ther
13
115
124
5. VirolleT
AdamsonEd
BaronV
BirleD
MercolaD
2001
The Egr-1 Transcription Factor Directly Activates Pten During Irradiation-Induced Signalling.
Nat Cell Biol
3
1124
1128
6. SalmenaL
CarracedoA
PandolfiPp
2008
Tenets Of Pten Tumor Suppression.
Cell
133
403
414
7. BrunetA
BonniA
ZigmondMj
LinMz
JuoP
1999
Akt Promotes Cell Survival By Phosphorylating And Inhibiting A Forkhead Transcription Factor.
Cell
96
857
868
8. GarberMe
JonesKa
1999
Hiv-1 Tat: Coping With Negative Elongation Factors.
Curr Opin Immunol
11
460
465
9. HottigerMo
NabelGj
1998
Interaction Of Human Immunodeficiency Virus Type 1 Tat With The Transcriptional Coactivators P300 And Creb Binding Protein.
J Virol
72
8252
8256
10. MarzioG
TyagiM
GutierrezMi
GiaccaM
1998
Hiv-1 Tat Transactivator Recruits P300 And Creb-Binding Protein Histone Acetyltransferases To The Viral Promoter.
Proc Natl Acad Sci U S A
95
13519
13524
11. OttM
SchnolzerM
GarnicaJ
FischleW
EmilianiS
1999
Acetylation Of The Hiv-1 Tat Protein By P300 Is Important For Its Transcriptional Activity.
Curr Biol
9
1489
1492
12. SilvermanEs
DuJ
WilliamsAj
WadgaonkarR
DrazenJm
1998
Camp-Response-Element-Binding-Protein-Binding Protein (Cbp) And P300 Are Transcriptional Co-Activators Of Early Growth Response Factor-1 (Egr-1).
Biochem J
336
Pt 1
183
189
13. DengL
WangD
De La FuenteC
WangL
LiH
2001
Enhancement Of The P300 Hat Activity By Hiv-1 Tat On Chromatin Dna.
Virology
289
312
326
14. KwonHs
BrentMm
GetachewR
JayakumarP
ChenLf
2008
Human Immunodeficiency Virus Type 1 Tat Protein Inhibits The Sirt1 Deacetylase And Induces T Cell Hyperactivation.
Cell Host Microbe
3
158
167
15. WestendorpMo
FrankR
OchsenbauerC
StrickerK
DheinJ
1995
Sensitization Of T Cells To Cd95-Mediated Apoptosis By Hiv-1 Tat And Gp120.
Nature
375
497
500
16. HudsonL
LiuJ
NathA
JonesM
RaghavanR
2000
Detection Of The Human Immunodeficiency Virus Regulatory Protein Tat In Cns Tissues.
J Neurovirol
6
145
155
17. FrankelAd
PaboCo
1988
Cellular Uptake Of The Tat Protein From Human Immunodeficiency Virus.
Cell
55
1189
1193
18. CuiM
HuangY
ZhaoY
ZhengJ
2008
Transcription Factor Foxo3a Mediates Apoptosis In Hiv-1-Infected Macrophages.
J Immunol
180
898
906
19. Van GrevenyngheJ
ProcopioFa
HeZ
ChomontN
RiouC
2008
Transcription Factor Foxo3a Controls The Persistence Of Memory Cd4(+) T Cells During Hiv Infection.
Nat Med
14
266
274
20. McneesAl
MahrJa
OrnellesD
GoodingLr
2004
Postinternalization Inhibition Of Adenovirus Gene Expression And Infectious Virus Production In Human T-Cell Lines.
J Virol
78
6955
6966
21. WongK
SharmaA
AwasthiS
MatlockEf
RogersL
2005
Hiv-1 Tat Interactions With P300 And Pcaf Transcriptional Coactivators Inhibit Histone Acetylation And Neurotrophin Signaling Through Creb.
J Biol Chem
280
9390
9399
22. BresV
TagamiH
PeloponeseJm
LoretE
JeangKt
2002
Differential Acetylation Of Tat Coordinates Its Interaction With The Co-Activators Cyclin T1 And Pcaf.
Embo J
21
6811
6819
23. GarciaJa
HarrichD
PearsonL
MitsuyasuR
GaynorRb
1988
Functional Domains Required For Tat-Induced Transcriptional Activation Of The Hiv-1 Long Terminal Repeat.
Embo J
7
3143
3147
24. EfthymiadisA
BriggsLj
JansDa
1998
The Hiv-1 Tat Nuclear Localization Sequence Confers Novel Nuclear Import Properties.
J Biol Chem
273
1623
1628
25. RenB
RobertF
WyrickJj
AparicioO
JenningsEg
2000
Genome-Wide Location And Function Of Dna Binding Proteins.
Science
290
2306
2309
26. MarsonA
KretschmerK
FramptonGm
JacobsenEs
PolanskyJk
2007
Foxp3 Occupancy And Regulation Of Key Target Genes During T-Cell Stimulation.
Nature
445
931
935
27. ZhangX
GuoC
ChenY
ShulhaHp
SchnetzMp
2008
Epitope Tagging Of Endogenous Proteins For Genome-Wide Chip-Chip Studies.
Nat Methods
5
163
165
28. GeorgescuMm
KirschKh
AkagiT
ShishidoT
HanafusaH
1999
The Tumor-Suppressor Activity Of Pten Is Regulated By Its Carboxyl-Terminal Region.
Proc Natl Acad Sci U S A
96
10182
10187
29. ShanX
CzarMj
BunnellSc
LiuP
LiuY
2000
Deficiency Of Pten In Jurkat T Cells Causes Constitutive Localization Of Itk To The Plasma Membrane And Hyperresponsiveness To Cd3 Stimulation.
Mol Cell Biol
20
6945
6957
30. WangSs
EsplinEd
LiJl
HuangL
GazdarA
1998
Alterations Of The Ppp2r1b Gene In Human Lung And Colon Cancer.
Science
282
284
287
31. ColellaS
OhgakiH
RuedigerR
YangF
NakamuraM
2001
Reduced Expression Of The Aalpha Subunit Of Protein Phosphatase 2a In Human Gliomas In The Absence Of Mutations In The Aalpha And Abeta Subunit Genes.
Int J Cancer
93
798
804
32. JanssensV
GorisJ
2001
Protein Phosphatase 2a: A Highly Regulated Family Of Serine/Threonine Phosphatases Implicated In Cell Growth And Signalling.
Biochem J
353
417
439
33. SilversteinAm
BarrowCa
DavisAj
MumbyMc
2002
Actions Of Pp2a On The Map Kinase Pathway And Apoptosis Are Mediated By Distinct Regulatory Subunits.
Proc Natl Acad Sci U S A
99
4221
4226
34. YangJ
WuJ
TanC
KleinPs
2003
Pp2a:B56epsilon Is Required For Wnt/Beta-Catenin Signaling During Embryonic Development.
Development
130
5569
5578
35. LetourneuxC
RocherG
PorteuF
2006
B56-Containing Pp2a Dephosphorylate Erk And Their Activity Is Controlled By The Early Gene Iex-1 And Erk.
Embo J
25
727
738
36. MoorheadGb
Trinkle-MulcahyL
Ulke-LemeeA
2007
Emerging Roles Of Nuclear Protein Phosphatases.
Nat Rev Mol Cell Biol
8
234
244
37. JinZ
ShiJ
SarafA
MeiW
ZhuGz
2009
The 48-Kda Alternative Translation Isoform Of Pp2a:B56epsilon Is Required For Wnt Signaling During Midbrain-Hindbrain Boundary Formation.
J Biol Chem
284
7190
7200
38. SatoS
FujitaN
TsuruoT
2000
Modulation Of Akt Kinase Activity By Binding To Hsp90.
Proc Natl Acad Sci U S A
97
10832
10837
39. ResjoS
GoranssonO
HarndahlL
ZolnierowiczS
ManganielloV
2002
Protein Phosphatase 2a Is The Main Phosphatase Involved In The Regulation Of Protein Kinase B In Rat Adipocytes.
Cell Signal
14
231
238
40. TrotmanLc
AlimontiA
ScaglioniPp
KoutcherJa
Cordon-CardoC
2006
Identification Of A Tumour Suppressor Network Opposing Nuclear Akt Function.
Nature
441
523
527
41. YanL
LavinVa
MoserLr
CuiQ
KaniesC
2008
Pp2a Regulates The Pro-Apoptotic Activity Of Foxo1.
J Biol Chem
283
7411
7420
42. BertoliC
CopettiT
LamEw
DemarchiF
SchneiderC
2009
Calpain Small-1 Modulates Akt/Foxo3a Signaling And Apoptosis Through Pp2a.
Oncogene
28
721
733
43. YinKj
HsuCy
HuXy
ChenH
ChenSw
2006
Protein Phosphatase 2a Regulates Bim Expression Via The Akt/Fkhrl1 Signaling Pathway In Amyloid-Beta Peptide-Induced Cerebrovascular Endothelial Cell Death.
J Neurosci
26
2290
2299
44. BarreyroFj
KobayashiS
BronkSf
WerneburgNw
MalhiH
2007
Transcriptional Regulation Of Bim By Foxo3a Mediates Hepatocyte Lipoapoptosis.
J Biol Chem
282
27141
27154
45. DubrovskaA
KimS
SalamoneRj
WalkerJr
MairaSm
2009
The Role Of Pten/Akt/Pi3k Signaling In The Maintenance And Viability Of Prostate Cancer Stem-Like Cell Populations.
Proc Natl Acad Sci U S A
106
268
273
46. LeiH
QuelleFw
2009
Foxo Transcription Factors Enforce Cell Cycle Checkpoints And Promote Survival Of Hematopoietic Cells After Dna Damage.
Mol Cancer Res
7
1294
1303
47. EssaghirA
DifN
MarbehantCy
CofferPj
DemoulinJb
2009
The Transcription Of Foxo Genes Is Stimulated By Foxo3 And Repressed By Growth Factors.
J Biol Chem
284
10334
10342
48. LiCj
FriedmanDj
WangC
MetelevV
PardeeAb
1995
Induction Of Apoptosis In Uninfected Lymphocytes By Hiv-1 Tat Protein.
Science
268
429
431
49. NekhaiS
JerebtsovaM
JacksonA
SoutherlandW
2007
Regulation Of Hiv-1 Transcription By Protein Phosphatase 1.
Curr Hiv Res
5
3
9
50. BharuchaDc
ZhouM
NekhaiS
BradyJn
ShuklaRr
2002
A Protein Phosphatase From Human T Cells Augments Tat Transactivation Of The Human Immunodeficiency Virus Type 1 Long-Terminal Repeat.
Virology
296
6
16
51. RuedigerR
BrewisN
OhstK
WalterG
1997
Increasing The Ratio Of Pp2a Core Enzyme To Holoenzyme Inhibits Tat-Stimulated Hiv-1 Transcription And Virus Production.
Virology
238
432
443
52. ChenD
WangM
ZhouS
ZhouQ
2002
Hiv-1 Tat Targets Microtubules To Induce Apoptosis, A Process Promoted By The Pro-Apoptotic Bcl-2 Relative Bim.
Embo J
21
6801
6810
53. MottaMc
DivechaN
LemieuxM
KamelC
ChenD
2004
Mammalian Sirt1 Represses Forkhead Transcription Factors.
Cell
116
551
563
54. RahlPb
LinCy
SeilaAc
FlynnRa
MccuineS
C-Myc Regulates Transcriptional Pause Release.
Cell
141
432
445
55. ZhouQ
YikJh
2006
The Yin And Yang Of P-Tefb Regulation: Implications For Human Immunodeficiency Virus Gene Expression And Global Control Of Cell Growth And Differentiation.
Microbiol Mol Biol Rev
70
646
659
56. YangZ
YikJh
ChenR
HeN
JangMk
2005
Recruitment Of P-Tefb For Stimulation Of Transcriptional Elongation By The Bromodomain Protein Brd4.
Mol Cell
19
535
545
57. YikJh
ChenR
NishimuraR
JenningsJl
LinkAj
2003
Inhibition Of P-Tefb (Cdk9/Cyclin T) Kinase And Rna Polymerase Ii Transcription By The Coordinated Actions Of Hexim1 And 7sk Snrna.
Mol Cell
12
971
982
58. BarboricM
YikJh
CzudnochowskiN
YangZ
ChenR
2007
Tat Competes With Hexim1 To Increase The Active Pool Of P-Tefb For Hiv-1 Transcription.
Nucleic Acids Res
35
2003
2012
59. ChartierC
DegryseE
GantzerM
DieterleA
PaviraniA
1996
Efficient Generation Of Recombinant Adenovirus Vectors By Homologous Recombination In Escherichia Coli.
J Virol
70
4805
4810
60. LeeTi
JohnstoneSe
YoungRa
2006
Chromatin Immunoprecipitation And Microarray-Based Analysis Of Protein Location.
Nat Protoc
1
729
748
61. SmithJl
FreebernWj
CollinsI
De SierviA
MontanoI
2004
Kinetic Profiles Of P300 Occupancy In Vivo Predict Common Features Of Promoter Structure And Coactivator Recruitment.
Proc Natl Acad Sci U S A
101
11554
11559
62. EmerlingBm
WeinbergF
LiuJl
MakTw
ChandelNs
2008
Pten Regulates P300-Dependent Hypoxia-Inducible Factor 1 Transcriptional Activity Through Forkhead Transcription Factor 3a (Foxo3a).
Proc Natl Acad Sci U S A
105
2622
2627
63. YuJ
De BelleI
LiangH
AdamsonEd
2004
Coactivating Factors P300 And Cbp Are Transcriptionally Crossregulated By Egr1 In Prostate Cells, Leading To Divergent Responses.
Mol Cell
15
83
94
64. HughesJd
EstepPw
TavazoieS
ChurchGm
2000
Computational Identification Of Cis-Regulatory Elements Associated With Groups Of Functionally Related Genes In Saccharomyces Cerevisiae.
J Mol Biol
296
1205
1214
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 9
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens
- The Length of Vesicular Stomatitis Virus Particles Dictates a Need for Actin Assembly during Clathrin-Dependent Endocytosis
- Inhibition of TIR Domain Signaling by TcpC: MyD88-Dependent and Independent Effects on Virulence
- Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes