Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TRANSCRIPTION FACTORS

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Structural groups of transcription factors• Helix-loop-helix eg. MyoD, c-Myc• Leucin zippers eg. AP-1, CREB• Zinc-coordinating DNA-binding domains eg.

Zinc fingers: nuclear receptors for steroids, thyroid hormone; GATA factors

• Helix-turn-helix eg. Homeobox; Forkhead / winged helix

• Beta-scaffold factors with minor groove contacts eg. NFkB, NFAT, STAT, p53

• Others

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Structural groups of transcription factors

CC

HH

CC

HH

DNA binding

Zinc finger transcription factors

TransactivationTransactivation

Zn

Zn

Basic helix-loop-helix

HelixHelix

HelixHelix

DNA-bindingdomain

DNA-bindingdomain

LoopLoop

H2NNH2

Basic leucine zipper

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Functional domains of transcription factors

Ligand

A/B C E FDN-terminal domain Hinge region C-terminal domain

DNA binding domain (DBD) Ligand binding domain (LBD)

DimerizationTransactivation

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Nuclear receptor superfamily

GR GR

Steroid Recetors

GlucocorticoidMineralocorticoidProgesteroneAndrogen

GRMRPRAR

Dimeric Orphan Receptors

RXRCOUPHNF-4TR2TLXGCNF

9-cis RARXRRXR

Monomeric/Tethered Orphan Receptors

NGFI-BSF-1Rev-erbRORERR

RXR

T3RRARVDRPPAR

PPAR

EcRFXRCARLXRPXR/SXR

RXR Heterodimers

Thyroid hormoneAll-trans RA1,2,5-(OH)2-VDFatty acids15d-12,14-PGJEcdysoneBile acidsAndrostaneOxysterolXenobiotics

RXR R

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Mechanism of steroid receptor action

HSPGRGRGR

HSP

GR

HRE

Co-activatorRNA

polymeraseGRGR

Co-activator

RNApolymerase

Co-activatorRNA

polymeraseRXR R

HRE

Co-activator

RNApolymerase

Co-activatorRNA

polymerase

HRE

RXRRXR

Co-repressor

Hormone

Nucleus

Plasma membrane

Cytoplasm

Co-repressorRXR R

HRE

Transcription Transcription Transcription

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Functional groups of TFs• General transcription factors: constitutively

active, present in all cells at all times, bind TATA box, form preinitiation complex eg. TFIIA-H

• Specific transcription factors /upstream transcription factors are conditionally active– Developmental (cell specific) eg. GATA,

MyoD, Hox, Winged helix– Signal-dependent

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Signal-dependent TFs

• Extracellular ligand (eg. nuclear receptors)• Intracellular ligand (eg. SREBP, p53)• Cell-membrane receptor dependent• Resident nuclear (eg. CREB, AP-1, Mef-

2)• Latent cytoplasmic (eg. STAT, NFAT,

NFkB, Notch)

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TFs in T cell activation induce cytokine production

TCR

b

d e e zz

CD28

Plasma membrane

Calcium flux,NFAT activation

MAPK activation,AP1 formation

GRB2

SOS

RAS

RASGRP1

DAG

GTP

NFAT FOS JUN IL-12Nucleus

ZAP70

AP1

CD3

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Structure of STATs

NH2 Coiled coil DBD Lk SH2 TADYP

0 200 400 600 800

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Regulation of transcription

Transcriptional controlTranscription factors, chromatin state,

combinatorial control, co-factors, alternative promoters, etc.

Post-transcriptional controlMicroRNAs, alternative splicing, alternative polyadenylation,

RNA-binding proteins, etc.

miRNAs

mRNAsTF TF

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Mechanism of gene regulation• General transcription factors and the RNA

Polymerase interacts with numerous coregulators (specific transcription factors)

• Activators bind to enhancer elements• Repressors bind to silencer elements of the

DNA upstream from the TATA box

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Growth factor induced TFs and their biological effect

Cell survival Proliferation Apoptosis resistance

Metastasis Angiogenesis

SOSGRB2 Ras Rac RhoCDC42

MEK1/2

Erk

Raf

ERK pathway

MKK4/7

JNK

MEKK

JNK pathway

MKK3/6

p38

Tak

p38 pathway

Akt

mTor

PI3K

HER2

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Some important transcription factors

Family Representative transcription factors Functions

Homeodomain

Hox Hoxa-1, Hoxb-2, etc. Axis formation

POU Pit-1, Unc-86, Oct-2 Pituitary development; neural fate

LIM Lim-1, Forkhead Head development

Pax Pax1, 2, 3, etc. Neural specification; eye development

Basic helix-loop-helix (bHLH) MyoD, achaete, daughterlessMuscle and nerve specification; Drosophila sex determination

Basic leucine zipper (bZip) C/EBP, AP1 Liver differentiation; fat cell specification

Zinc finger

Standard WT1, Krüppel, EngrailedKidney, gonad, and macrophage development; Drosophila segmentation

Nuclear hormone receptorsGlucocorticoid receptor, estrogen receptor, testosterone receptor, retinoic acid receptors

Secondary sex determination; craniofacial development; limb development

Sry-Sox Sry, SoxD, Sox2Bend DNA; mammalian primary sex determination; ectoderm differentiation

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Transcription factors and diseases• IPEX syndrome (Immunodysregulation

Polyendocrinopathy Enteritis X-linked), “Scurfy” phenotype in mouse: FoxP3

• Rett-syndrome: MECP2 • Li-Fraumeni-syndrome: p53