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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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

slide16

ARNT interacts

with the LBD of

ERa/b

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

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

slide27

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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