cellular signal transduction 2) from the membrane to the nucleus teil f transcription factors and...
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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
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
SMAD
SMAD/Co-SMAD
SMAD
STATSTATA-Cyclase PLC Ras
STAT
cAMP
Signaling pathways: Receptor to transcription factors
PKA
SRF
IKKK
NFAT / NFB
Gene regulation by PKA:
CREB bound to CREIs phosphorylated by PKA,activates transcription without effect on DNA binding
Example 3
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
Ca++
Calmodulin
Calcineurin
NFAT
PI
Ca++ Signaling pathway - Gene regulation
the PhosphataseCalcineurindephosphorylatesNFAT
NFAT translocatesInto nucleus
NFAT= transcription factor(nuclear factoractivated T cell) Kern
P
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
(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
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
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
The nuclear localization signal is a basic amino acid sequence
Model of nuclear importMediated by the small G-protein Ran
Ac
Ac
HAT
HDAC
condensed 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
A
REPRESSION
ACTIVIERUNG
HDAC
X
Y
HAT
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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