Download Transcription Factors

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
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
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
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Tímea Berki and Ferenc Boldizsár
Signal transduction
TRANSCRIPTION
FACTORS
Structural groups of
transcription factors
TÁMOP-4.1.2-08/1/A-2009-0011
• 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
Structural groups of
transcription factors
Basic helix-loop-helix
Helix
Loop
Helix
Zinc finger transcription factors
Helix
C
Loop
Helix
C
Transactivation
Zn
H
H
C
C
Zn
NH2
DNA-binding
domain
H2N
H
H
DNA binding
Basic leucine zipper
DNA-binding
domain
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Transactivation
Functional domains of
transcription factors
Transactivation
Dimerization
Hinge region
N-terminal domain
A/B
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C
D
DNA binding domain (DBD)
C-terminal domain
F
E
Ligand binding domain (LBD)
Ligand
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Nuclear receptor
superfamily
Steroid Recetors
RXR Heterodimers
GR
Glucocorticoid
T3R
Thyroid hormone
MR
Mineralocorticoid
RAR
All-trans RA
PR
Progesterone
VDR
1,2,5-(OH)2-VD
AR
Androgen
PPAR
Fatty acids
PPAR
15d-12,14-PGJ
EcR
Ecdysone
FXR
Bile acids
CAR
Androstane
LXR
Oxysterol
PXR/SXR
Xenobiotics
GR
GR
Dimeric Orphan Receptors
RXR
COUP
HNF-4
TR2
TLX
GCNF
RXR
Monomeric/Tethered Orphan Receptors
9-cis RA
RXR
RXR
NGFI-B
SF-1
Rev-erb
ROR
ERR
RXR
R
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Mechanism of steroid
receptor action
Hormone
Plasma membrane
Cytoplasm
HSP
GR
GR
GR
HSP
GR
Nucleus
RXR
Co-repressor
R
Co-activator
RNA
polymerase
Co-activator
HRE
RNA
polymerase
Co-repressor
Co-activator
GR
RNA
Transcription
polymerase
GR
HRE
RXR
HRE
Co-activator
R
RNA
Transcription
polymerase
RXR
Co-activator
RXR
RNA
Transcription
polymerase
HRE
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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
CD3
CD28
 b
Plasma membrane
d e e 
zz
DAG
GRB2
ZAP70
SOS
RAS
GTP
RAS
GRP1
Calcium flux, MAPK activation,
NFAT activation AP1 formation
AP1
Nucleus
NFAT
FOS
JUN
IL-12
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Structure of STATs
P
NH2
0
Coiled coil
200
DBD
400
Lk
SH2
600
Y
TAD
800
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Regulation of transcription
Post-transcriptional control
MicroRNAs, alternative splicing, alternative polyadenylation,
RNA-binding proteins, etc.
miRNAs
TF
TF
Transcriptional control
Transcription factors, chromatin state,
combinatorial control, co-factors, alternative promoters, etc.
mRNAs
Mechanism of gene
regulation
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• 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
HER2
GRB2
SOS
Ras
Rac
CDC42
Rho
ERK pathway
JNK pathway
p38 pathway
Raf
MEKK
Tak
PI3K
MEK1/2
MKK4/7
MKK3/6
Akt
Erk
JNK
p38
mTor
Cell survival
Proliferation
Metastasis
Apoptosis resistance
Angiogenesis
Some important
transcription factors
Family
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Representative transcription factors
Functions
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
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
Homeodomain
Zinc finger
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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