CELLULAR SIGNAL TRANSDUCTION 2) From the membrane to the nucleus TEIL F
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CELLULAR SIGNAL TRANSDUCTION2) From the membrane to the nucleus
TEIL F
TRANSCRIPTION FACTORS AND THE REGULATION OF TRANSCRIPTION
Rainer deMartin / Erhard HoferInstitute of Vascular Biology and Thrombosis Research
Vienna Competence CenterLazarettgasse 19, 1090 Wien
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Erhard Hoferactivation of transcription factors by surface receptors
Summary selected examplesCREB, SRF, NFAT, SMAD
additional specific example: - Regulation of signaling pathways/transcription factorsby proteolytic cleavage:WNT, NOTCH (embryonic development, adult stem cells)
Nuclear import, -export
Chromatin
Transcription initiation complexes
Rainer deMartin:Principals of transcriptional regulationStructural features of transcription factorsBasic mechanisms of transcriptional regulation
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SMAD
SMAD/Co-SMAD
SMAD
STATSTATA-Cyclase PLC Ras
STAT
cAMP
Signaling pathways: Receptor to transcription factors
PKA
SRF
IKKK
NFAT / NFB
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CREB, SRF, NFAT, SMAD
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Gene regulation by PKA:
CREB bound to CREIs phosphorylated by PKA,activates transcription without effect on DNA binding
Example 3
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The phosphorylated MAPK ERK is transported into the nucleus and phosphorylates the transcription factor TCF on the promoter
ERK: extracellular signal regulated kinaseTCF: ternary complex factorSRF: serum response factorSRE: serum response element
(DNA binding sequence for TCF and SRF in promoter of various genes)
Genes forCell cycle/Proliferationearly responsegenes, c-fos
or:PLC-RafMEK
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Ca++
Calmodulin
Calcineurin
NFAT
PI
Ca++ Signaling pathway - Gene regulation
the PhosphataseCalcineurindephosphorylatesNFAT
NFAT translocatesInto nucleus
NFAT= transcription factor(nuclear factoractivated T cell) Kern
P
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Transport ofphosphorylated SMADs into nucleus
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Regulation of transcription factors by proteolytic cleavage
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WNT signaling pathway
Secreted signaling peptide,important in embryonic developmentMutatios on proteins of wnt signaling pathway frequent in cancer
Example 4a Wnt Wingless (Drosophila)Int-1 (breast cancer oncogen) (detected experimentally by virus Integration)
In signalling pathway:APC (adenomoteous polyposis coli)mutated in adenoma of colonand 80 % of colon cancer
induces myc geneand proliferation
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(LDL rceptor related protein)
(Signaling protein)
(Corepressor)
-Catenin signaling pathway: w/o signal: -catenin is continously phosphorylated, ubiquitinylated, degraded in proteasomWnt-signal: Kinase is inhibited, non-phosphorylated -Catenin transported into nucleus, aktivates transcription by competing of a corepressor
(-Catenin Coaktivator)
Phosphorylation,Ubiquitinylation,degradation in proteasom
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components of the WNT signaling pathways e.g. important for maintaining the stem cell population in gastro-intestinal tract,Over-activation by APC mutation - cancer
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Notchhedgehog
1- Embryonic developmentE.g. nerve cells Drosophila,Delta on nerve cells signals to neighbouring cell: Do not differentiate to nerve cell,Peptide translocates into nucleus and convertsCSL to become an activator
2- Angiogenesis: Tip versus stalk cell, tip cell signals stalk cell not to become another tip cell
example 5b
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Nuclear import / -export
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Nuclear membrane:Double membrane with nuclear pores
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26 nm
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Nuclear pore complex
innere Seite
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The nuclear localization signal is a basic amino acid sequence
Model of nuclear importMediated by the small G-protein Ran
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Model of nuclear import and export
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CHROMATIN
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Summary
Interphase
Metaphase
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Eigenschaften von Insulatorelementen
model
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Change of chromatin structure by activator protein
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Ac
Ac
HAT
HDACcondensed CHROMATIN
no TRANScRIPTION
Z.B. HETEROCHROMATIN
loose CHROMATIN
TRANCRIPTION
Z.B. EUCHROMATIN
HAT = HISTONACETYLTRANSFERASE ACTIVATOR OF TRANSCRIPTION
HDAC = HISTONDEACETYLASE REPRESSOR of TRANSCRIPTION
DNADNA
NUCLEOSOM
CHROMATINCHROMATIN
GENEXCS18
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A
REPRESSION
ACTIVIERUNG
HDACX
YHAT
Target GENE
Target GENE
Z
REGULATION OF TRANSCRIPTION BY REGULATION OF TRANSCRIPTION BY CHANGE OF CHROMATIN STRUCTURCHANGE OF CHROMATIN STRUCTUR
condensed Chromatin
open Chromatin
Repressor
Aktivator
GENEXCS19
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Gene regulatory proteins form frequently large
complexes
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DNA Looping
Mediator
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Gene expression
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