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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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(1)

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

TRANSCRIPTION FACTORS

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

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

(4)

Structural groups of transcription factors

C C

H H

C C

H H

DNA binding

Zinc finger transcription factors

Transactivation Transactivation

Zn Zn

Basic helix-loop-helix

Helix Helix

Helix Helix

DNA-binding domain DNA-binding

domain

Loop Loop

H

2

N NH

2

Basic leucine zipper

(5)

Functional domains of transcription factors

Ligand

A/B C D E F

N-terminal domain Hinge region C-terminal domain

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

Transactivation

(6)

Nuclear receptor superfamily

GR GR

Steroid Recetors

Glucocorticoid Mineralocorticoid Progesterone Androgen GR

MR PR AR

Dimeric Orphan Receptors

RXR COUP HNF-4 TR2 TLX GCNF

9-cis RA

RXR RXR

Monomeric/Tethered Orphan Receptors

NGFI-B SF-1 Rev-erb ROR ERR

RXR T3R

RAR VDR PPAR

PPAR

EcR FXR CAR LXR PXR/SXR

RXR Heterodimers

Thyroid hormone All-trans RA 1,2,5-(OH)2-VD Fatty acids 15d-12,14-PGJ Ecdysone Bile acids Androstane Oxysterol Xenobiotics

RXR R

(7)

Mechanism of steroid receptor action

HSP GR GR

GR

HSP

GR

HRE

Co-activator RNA polymerase GR

GR

Co-activator

RNA polymerase

Co-activator RNA polymerase RXR R

HRE

Co-activator

RNA polymerase

Co-activator RNA polymerase

HRE RXR RXR

Co-repressor Hormone

Nucleus Plasma membrane

Cytoplasm

Co-repressor RXR R

HRE

Transcription Transcription Transcription

(8)

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

(9)

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)

(10)

TFs in T cell activation induce cytokine production

TCR

 b

d e e z z

CD28

Plasma membrane

Calcium flux, NFAT activation

MAPK activation, AP1 formation GRB2

SOS

RAS

RAS GRP1

DAG

GTP

NFAT FOS JUN IL-12

Nucleus

ZAP70

AP1 CD3

(11)

Structure of STATs

NH

2

Coiled coil DBD Lk SH

2

Y TAD

P

0 200 400 600 800

(12)

Regulation of transcription

Transcriptional control

Transcription factors, chromatin state,

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

Post-transcriptional control

MicroRNAs, alternative splicing, alternative polyadenylation, RNA-binding proteins, etc.

miRNAs

mRNAs

TF TF

(13)

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

(14)

Growth factor induced TFs and their biological effect

Cell survival Proliferation Apoptosis resistance

Metastasis Angiogenesis

SOS

GRB2 Ras Rac CDC42 Rho

MEK1/2

Erk Raf ERK pathway

MKK4/7

JNK MEKK JNK pathway

MKK3/6

p38 Tak p38 pathway

Akt

mTor PI3K

HER2

(15)

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, daughterless Muscle and nerve specification; Drosophila sex determination

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

Standard WT1, Krüppel, Engrailed Kidney, gonad, and macrophage

development; Drosophila segmentation Nuclear hormone receptors Glucocorticoid receptor, estrogen receptor,

testosterone receptor, retinoic acid receptors Secondary sex determination; craniofacial development;

limb development

Sry-Sox Sry, SoxD, Sox2 Bend DNA; mammalian primary sex determination;

ectoderm differentiation

(16)

Transcription factors and diseases

• IPEX syndrome (Immunodysregulation

Polyendocrinopathy Enteritis X-linked), “Scurfy”

phenotype in mouse: FoxP3

• Rett-syndrome: MECP2

• Li-Fraumeni-syndrome: p53

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