The bhlh pas protein arnt effects on er signalling
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The bHLH-PAS protein ARNT - effects on ER signalling. Biological Effects of Dioxin. Toxic Effects: Wasting, lymph atrophy, endometriosis, etc Teratogenic Effects Tumor Promotion Enzyme Induction Interference with Hormonal signaling (EDC). The bHLH-PAS proteins. Dimerization

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The bHLH-PAS protein ARNT - effects on ER signalling

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The bhlh pas protein arnt effects on er signalling

The bHLH-PAS protein ARNT - effects on ER signalling


Biological effects of dioxin

Biological Effects of Dioxin

  • Toxic Effects: Wasting, lymph atrophy, endometriosis, etc

  • Teratogenic Effects

  • Tumor Promotion

  • Enzyme Induction

  • Interference with Hormonal signaling (EDC)


The bhlh pas proteins

The bHLH-PAS proteins

Dimerization

DNA- and

hsp90 binding

Ligand- and

hsp90 binding

Examples:

Metabolism of xenobiotics

Partner for AhR and HIF-1a

CNS growth/differentiation

Regulation of circadian rhythm


Activation process of the ahr

Activation process of the AhR


A h r n uclear t ranslocator arnt

AhRNuclear Translocator: ARNT

  • Obligatory partner for DR and HIF-1a

  • Ligand  DR-ARNT dimers bind to xenobiotic response elements (XREs) of target genes

  • ARNT is constitutively expressed protein

  • Nuclear localization

  • 3 isoforms identified


Arnt isoforms

ARNT isoforms

  • ARNT-1: ubiquitously expressed

  • ARNT-2: in developing brain, kidney, heart

  • bMAL/ARNT-3: brain, muscle

bHLH

PAS1

PAS2

mARNT-1

791 aa

57%

95%

78%

mARNT-2

712 aa

34%

39%

63%

bMAL/mARNT-3

632 aa


Nuclear receptor superfamily

Nuclear receptor superfamily

Nuclear receptor superfamily

Nuclear receptor superfamily

A/B C D E

A/B C D E

A/B C D E

AF-1 DBD Hinge LBD AF-2

AF-1 DBD Hinge LBD AF-2

AF-1 DBD Hinge LBD AF-2

Ligand regulate receptors like steroid receptors, thyroid hormaone receptors, retinoid acid receptors and Vitamin D

Ligand regulate receptors like steroid receptors, thyroid hormaone receptors, retinoid acid receptors and Vitamin D

Ligand regulate receptors like steroid receptors, thyroid hormaone receptors, retinoid acid receptors and Vitamin D

Orpan receptors

Orpan receptors

Orpan receptors


Nuclear receptor signaling

Nuclear receptor signaling


Nuclear receptor co factors

Nuclear receptor co-factors

Coactivators: SRC family, CBP/p300, PBP, PCAF…

Corepressors: N-CoR, SMRT, DAX-1, SHP…


Src p160 co activator factors

SRC/p160 Co-activator factors

bHLHPAS

SRC-1

SCR2

(TIF-2)

SRC-3

NR-box


Arnt regulates multiple pathways

p23

hsp90

XAP-2

A

B

ARNT regulates multiple pathways

DR

A

B

ARNT

p23

hsp90

Other nuclear receptors?

Other transcription factors?

A

B

HIF-1a


Er a and arnt interact

ERa and ARNT interact

pSG5-Flag-

pSG5-Flag-ERa

pCMV-ARNT

-

-

E2

Tam

IP:anti-Flag

ARNT

WCEs: 10% of input

ARNT

Western: anti-ARNT


Er and arnt interact

ER and ARNT interact

pSG5-

pSG5-ERb

pCMV-ARNT

-

-

E2

Tam

IP:ERb mAb

ARNT

ARNT

WCEs: 10% input

Western: anti-ARNT


Arnt stimulates er activity

ARNT stimulates ER activity

ARNT

TIF-2


Arnt stimulates er activity1

ARNT stimulates ER activity

ARNT

TIF-2


The bhlh pas protein arnt effects on er signalling

ARNT interacts

with the LBD of

ERa/b


The c terminal domain of arnt is required for co activation

The C-Terminal domain of ARNT is required for co-activation


Arnt is recruited to the ps2 promoter

pS2

ERE

ARNT is recruited to the pS2 promoter

+ E2

PCR products

-54

-353


Tcdd and 3 mc inhibit ers transcriptional activity in hc11 cells

TCDD and 3-MC inhibit ERs transcriptional activity in HC11 cells

PPT

E2

DPN


3 mc but not tcdd activates ers

3-MC but not TCDD activates ERs

-

E2

3-MC


Antiestrogens inhibit 3 mc induced transcriptional activity

Antiestrogens inhibit 3-MC induced transcriptional activity


Hypoxia and tcdd inhibit er transcriptional activity in hc11 cells

Hypoxia and TCDD inhibit ER transcriptional activity in HC11 cells


Activation of the ahr inhibits recruitment of arnt to e 2 regulated promoters

Activation of the AhR inhibits recruitment of ARNT to E2 regulated promoters

E2+

TCDD

E2+

TCDD

NH

E2

TCDD

Input

NH

E2

TCDD

Input

IgG

IgG

a-ERa

a-ARNT

ARNT

c-Fos

Lactoferrin

ERE

ERE

UTR


Effects of arnt si rna

Effects of ARNT Si-RNA


Summary

SUMMARY

  • ARNT interacts with ligand-activated ERa and ERb

  • ARNT stimulates both ERa and ERb transcriptional activity

  • ARNT is recruited to the E2 regulated promoters in an ligand-dependent manner


Arnt regulates multiple cellular pathways

p23

hsp90

XAP-2

A

B

ARNT regulates multiple cellular pathways

DR

ERa/b

A

B

ARNT

p23

hsp90

Other nuclear receptors?

Other transcription factors?

A

B

HIF-1a


The bhlh pas protein arnt effects on er signalling

Pauliina Pentinen / Sari Mäkele

University of Turku

Juliette Rambaud / Vincent Laudet

Ecole Normale Supérieure de Lyon

Ingemar Pongratz

Katarina Pettersson

Sara Brunnberg

Elin Swedenborg

Wen Cai

Petra Berg


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