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

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



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 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


ARNT interacts

with the LBD of

ERa/b



Arnt is recruited to the ps2 promoter

pS2

ERE

ARNT is recruited to the pS2 promoter

+ E2

PCR products

-54

-353






Activation of the ahr inhibits recruitment of arnt to e 2 regulated promoters
Activation of the AhR inhibits recruitment of ARNT to E cells2 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



Summary
SUMMARY cells

  • 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 cells

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


Pauliina Pentinen / Sari Mäkele cells

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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