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TGF-β Signaling Regulates the Expression of Multiple Target … · 2015. 7. 24. · Bcl-xL, Bcl-2...
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Target Genes Smad2/3 or Smad1/5/8 DNA-binding Transcription Factor Smad4 CoA CoR Chromatin Remodeling Factors PP2A p38 PAK2 ROCK1 PDK-1 MEK1/2 ERK1/2 Akt mTOR p70S6K Cdc42/Rac1 RhoA RhoA PI 3-K Ras Raf-1 TAK1 p38 MKK3/6 JNK JNK MKK4 Smurf1/2 Smurf1 SARA GRB2 TRAF-6 Shc Daxx Par6 SOS Smad7 Smad4 Smad2/3 Smad2/3 or Smad1/5/8 P P P P Smad2/3 Smad1/5/8 Smad1/5/8 P P Smad4 TGF-β RI TGF-β RIII or Endoglin TGF-β RII TGF-β Dimer Latent TGF-β P Smad4 DEGRADATION CLEAVAGE/ICD NUCLEAR TRANSLOCATION Ub Ub Ub Inhibits Cell Proliferation Induces Apoptosis Activates Autophagy Inhibits Growth Factors in the Tumor Stroma Inhibits Angiogenesis Suppresses Inflammation TGF-β Target Genes p15, p21, p57, 4EBP1 TGF-β Target Genes BIK, BIM, DAPK, Fas, GADD45β TGF-β Target Genes ATG5, ATG7, Beclin 1/ATG6, DAPK TGF-β Target Genes Thrombospondin TGF-β Target Genes FoxP3 ✗ TGF-β Target Genes CDC25A, E2F-1, Id1-3, c-Myc ✗ TGF-β Target Genes Bcl-xL, Bcl-2 ✗ TGF-β Target Genes HGF, MSP, TGF-α ✗ TGF-β Target Genes GATA-3, T-bet Promotes Cell Proliferation Suppresses the Immune Response Promotes Angiogenesis Promotes Cancer Stem Cell Self-Renewal Promotes the Epithelial-to- Mesenchymal Transition Promotes Metastasis TGF-β Target Genes PDGF-B TGF-β Target Genes FoxP3 TGF-β Target Genes VEGF, MMP-2, MMP-9 TGF-β Target Genes LIF, SOX4 TGF-β Target Genes Snail1/2, ZEB1/2, HMGA2 TGF-β Target Genes HDM2, MMP-9 ✗ TGF-β Target Genes Fas Ligand, GATA-3, Granzyme A/B, IFN-γ, MICA, NKG2D, Nkp30, Perforin, T-bet ✗ TGF-β Target Genes TIMP Transforming growth factor (TGF)-β is a multifunctional cytokine that can have either tumor-suppressing or tumor-promoting effects in a cell- and context-dependent manner. TGF-β signals through a heterotetrameric receptor complex composed of two type I and two type II transmembrane serine/threonine kinase receptors. Following ligand binding, the type II receptor (TGF-β RII) phosphorylates the type I receptor (TGF-β RI), leading to the recruitment and phosphorylation of Smad2 and Smad3 in most cell types, or Smad1, Smad5, and Smad8 in some cells depending on the type I receptor that is expressed. Activated Smad proteins associate with Smad4 and translocate to the nucleus, where they recruit additional transcriptional regulators, including DNA-binding transcription factors, co-activators, co-repressors, and chromatin remodeling factors, that control the expression of numerous target genes. Differential expression of these factors may be responsible for cell type-specific responses to TGF-β. While many of the tumor-suppressing and tumor-promoting effects of TGF-β have been shown to be directly dependent on Smad signaling, TGF-β can also activate a number of other signaling pathways, including Ras/MAPK, Par6, RhoA/ROCK1, PI 3-K/Akt, p38, and JNK, which may contribute to the cancer-related effects of TGF-β signaling in a Smad-dependent or Smad-independent manner. Activation of these signaling pathways is both cell type-specific and context-dependent. This mini poster highlights genes that are regulated by TGF-β signaling and the mechanisms by which these genes suppress or promote tumor formation and progression. Inhibits Cell Proliferation TGF-β inhibits cell proliferation by inducing the expression of 4EBP1 and the cyclin-dependent kinase (CDK) inhibitors, p15, p21, and p57. 4EBP1 binds to eukaryotic initiation factor 4E (eIF4E) and inhibits protein translation (bottom right panel), while p15, p21, and p57 prevent cell cycle progression by inhibiting the activities of CDK-cyclin complexes that are required for the G1/S transition (left panel). Additionally, TGF-β represses the expression of CDC25A phosphatase, which is also required for CDK-cyclin activation (left panel), and negatively regulates the expression of multiple other factors involved in driving cell cycle progression and cell proliferation, including the Id proteins (left panel), E2F (left panel), and c-Myc (top right panel). Tumor-Suppressing Effects of TGF-β Tumor-Promoting Effects of TGF-β Epithelial Cells Claudin Occludin aPKC Par6 Par3 Afadin p120 Vinculin Plakophilin Plakoglobin β-Catenin α-Catenin α-Actinin Actin Actin Nectin JAMs E-Cadherin Desmocollin Desmoglein ZO-1 ZO-1 ZO-3 ZO-2 TIGHT JUNCTION ADHERENS JUNCTION DESMOSOME Desmoplakin METASTATIC DISSEMINATION REPRESSION OF EPITHELIAL GENES ACTIVATION OF MESENCHYMAL GENES LOSS OF CELL-CELL CONTACTS EMT MOTILITY, INVASION E-Cadherin Plakoglobin Claudins Occludin Desmoplakin Plakophilin Cytokeratins Crumb3 Snail1/2 EPITHELIAL MARKERS Fibronectin Vitronectin N-Cadherin Collagens MMPs Twist ZEB1/2 Snail1/2 E-Cadherin Claudins ZO Plakophilin Crumb3 ZEB1/2 Vimentin N-Cadherin MMP-2 ZEB1/2 Snail1/2 Twist HMGA2 MESENCHYMAL MARKERS Normal Epithelial Cell-Cell Adhesion Complexes ✗ ✗ TGF-β TGF-β TGF-β TGF-β TGF-β TGF-β E-Cadherin HMGA2 TGF-β Stromal Fibroblast Primary Tumor ✗ TGF-β signaling in epithelial tumor cells promotes an epithelial-to-mesenchymal transition by inducing the expression of transcription factors, such as Snail1/2, ZEB1/2, and HMGA2, which repress the expression of epithelial cell adhesion proteins and induce the expression of mesenchymal proteins. These changes promote the loss of cell polarity and cell-cell contacts and lead to the acquisition of a migratory, invasive phenotype that may allow cancer cell dissemination. Promotes the Epithelial-to-Mesenchymal Transition S phase genes S phase genes p15, p16, p21 G1 ARREST E2F DP DP Rb bHLH Transcription Factor Rb G1 S Nucleus Ras Raf-1 p15 Cdc25a TGF-β TGF-β TGF-β TGF-β TGF-β TGF-β MEK1/2 ERK1/2 E2F E2F Rb Id Id2 Id2 Rb SOS Shc GRB2 Growth Factor CDK4/6 Cyclin D CDK2 Cyclin E p21 or p57 DP Max c-Myc p15 p21 Cell Proliferation ✗ Miz-1 c-Myc TGF-β 4EBP1 TRANSLATION INITIATION eIF4E Met-tRNA-elF2-GTP Complex mRNA 40S ribosome subunit TGF-β1 CELEBRATING 1985–2015 30 YEARS This illustration represents general processes suggested in the scientific literature and is not to be considered comprehensive nor definitive. ©2011, 2015 R&D Systems TGF-β Signaling Regulates the Expression of Multiple Target Genes with Tumor-Suppressing and Tumor-Promoting Effects Global [email protected] [email protected] North America TEL 800 343 7475 Europe | Middle East | Africa TEL +44 (0)1235 529449 China [email protected] TEL +86 (21) 52380373 Rest of World bio-techne.com/find-us/distributors TEL +1 612 379 2956 bio-techne.com LEARN MORE rndsystems.com/TGFbeta
Transcript of TGF-β Signaling Regulates the Expression of Multiple Target … · 2015. 7. 24. · Bcl-xL, Bcl-2...
Target Genes
Smad2/3 or Smad1/5/8
DNA-bindingTranscription Factor
Smad4
CoACoR
ChromatinRemodeling
Factors
PP2Ap38
PAK2ROCK1
PDK-1
MEK1/2
ERK1/2
Akt
mTORp70S6K
Cdc42/Rac1 RhoA
RhoA
PI 3-K
Ras
Raf-1
TAK1
p38
MKK3/6
JNK
JNK
MKK4
Smurf1/2
Smurf1
SARA
GRB2TRAF-6
ShcDaxx
Par6
SOS
Smad7
Smad4
Smad2/3
Smad2/3 or Smad1/5/8
PP
PP
Smad2/3
Smad1/5/8
Smad1/5/8
P P
Smad4
TGF-β RITGF-β RIII
or Endoglin
TGF-β RII
TGF-β DimerLatent TGF-β
P
Smad4
DEGRADATION
CLEAVAGE/ICD NUCLEAR TRANSLOCATIONUb
Ub Ub
Inhibits Cell Proliferation Induces Apoptosis Activates Autophagy
Inhibits Growth Factors in the Tumor
StromaInhibits
AngiogenesisSuppresses
Infl ammation
�
TGF-β Target Genes
TGF-β Target Genesp15, p21, p57, 4EBP1
�
TGF-β Target Genes
TGF-β Target GenesBIK, BIM, DAPK, Fas,
GADD45β �
TGF-β Target Genes
TGF-β Target GenesATG5, ATG7,
Beclin 1/ATG6, DAPK �
TGF-β Target Genes
TGF-β Target GenesThrombospondin
�
TGF-β Target Genes
TGF-β Target GenesFoxP3
�
TGF-β Target Genes
TGF-β Target Genes
CDC25A, E2F-1, Id1-3, c-Myc
�
TGF-β Target Genes
TGF-β Target Genes
Bcl-xL, Bcl-2
�
TGF-β Target Genes
TGF-β Target Genes
HGF, MSP, TGF-α
�
TGF-β Target Genes
TGF-β Target Genes
GATA-3, T-bet
Promotes Cell Proliferation
Suppresses the Immune Response
Promotes Angiogenesis
Promotes Cancer Stem Cell
Self-Renewal
Promotes the Epithelial-to-Mesenchymal
TransitionPromotes Metastasis
�
TGF-β Target Genes
TGF-β Target GenesPDGF-B
�
TGF-β Target Genes
TGF-β Target GenesFoxP3
�
TGF-β Target Genes
TGF-β Target GenesVEGF, MMP-2, MMP-9
�
TGF-β Target Genes
TGF-β Target GenesLIF, SOX4
�
TGF-β Target Genes
TGF-β Target GenesSnail1/2, ZEB1/2, HMGA2
�
TGF-β Target Genes
TGF-β Target GenesHDM2, MMP-9
�
TGF-β Target Genes
TGF-β Target Genes
Fas Ligand, GATA-3, Granzyme A/B, IFN-γ, MICA, NKG2D, Nkp30,
Perforin, T-bet
�
TGF-β Target Genes
TGF-β Target GenesTIMP
Transforming growth factor (TGF)-β is a multifunctional cytokine that can have either tumor-suppressing or tumor-promoting e� ects in a cell- and context-dependent manner. TGF-β signals through a heterotetrameric receptor complex composed of two type I and two type II transmembrane serine/threonine kinase receptors. Following ligand binding, the type II receptor (TGF-β RII) phosphorylates the type I receptor (TGF-β RI), leading to the recruitment and phosphorylation of Smad2 and Smad3 in most cell types, or Smad1, Smad5, and Smad8 in some cells depending on the type I receptor that is expressed. Activated Smad proteins associate with Smad4 and translocate to the nucleus, where they recruit additional transcriptional regulators, including DNA-binding transcription factors, co-activators, co-repressors, and chromatin remodeling factors, that control the expression of numerous target genes. Di� erential expression of these factors may be responsible for cell type-speci� c responses to TGF-β. While many of the tumor-suppressing and tumor-promoting e� ects of TGF-β have been shown to be directly dependent on Smad signaling, TGF-β can also activate a number of other signaling pathways, including Ras/MAPK, Par6, RhoA/ROCK1, PI 3-K/Akt, p38, and JNK, which may contribute to the cancer-related e� ects of TGF-β signaling in a Smad-dependent or Smad-independent manner. Activation of these signaling pathways is both cell type-speci� c and context-dependent. This mini poster highlights genes that are regulated by TGF-β signaling and the mechanisms by which these genes suppress or promote tumor formation and progression.
Inhibits Cell Proliferation
TGF-β inhibits cell proliferation by inducing the expression of 4EBP1 and the cyclin-dependent kinase (CDK) inhibitors, p15, p21, and p57. 4EBP1 binds to eukaryotic initiation factor 4E (eIF4E) and inhibits protein translation (bottom right panel), while p15, p21, and p57 prevent cell cycle progression by inhibiting the activities of CDK-cyclin complexes that are required for the G1/S transition (left panel). Additionally, TGF-β represses the expression of CDC25A phosphatase, which is also required for CDK-cyclin activation (left panel), and negatively regulates the expression of multiple other factors involved in driving cell cycle progression and cell proliferation, including the Id proteins (left panel), E2F (left panel), and c-Myc (top right panel).
Tumor-Suppressing Eff ects of TGF-β Tumor-Promoting Eff ects of TGF-β
Epithelial Cells
ClaudinOccludin
aPKC
Par6Par3
Afadin
p120
Vinculin
Plakophilin
Plakoglobin
β-Cateninα-Cateninα-Actinin
Actin
ActinNectin
JAMs
E-Cadherin
Desmocollin
Desmoglein
ZO-1
ZO-1
ZO-3
ZO-2TIGHT JUNCTION
ADHERENS JUNCTION
DESMOSOME Desmoplakin
METASTATICDISSEMINATION
REPRESSION OF EPITHELIAL GENESACTIVATION OF MESENCHYMAL GENES
LOSS OFCELL-CELLCONTACTS
EMT
MOTILITY, INVASION
E-CadherinPlakoglobinClaudinsOccludinDesmoplakinPlakophilinCytokeratinsCrumb3
Snail1/2EPITHELIAL MARKERS
FibronectinVitronectinN-CadherinCollagensMMPsTwistZEB1/2
Snail1/2E-CadherinClaudinsZOPlakophilinCrumb3
ZEB1/2 VimentinN-CadherinMMP-2
ZEB1/2 Snail1/2Twist
HMGA2MESENCHYMAL MARKERS
Normal Epithelial Cell-Cell Adhesion Complexes
� �
TGF-β TGF-β TGF-β
TGF-β
TGF-β TGF-β
E-CadherinHMGA2
TGF-β
MOTILITY, INVASIONMOTILITY, INVASIONMOTILITY, INVASIONMOTILITY, INVASIONMOTILITY, INVASION
Stromal Fibroblast
Primary Tumor
�
TGF-β signaling in epithelial tumor cells promotes an epithelial-to-mesenchymal transition by inducing the expression of transcription factors, such as Snail1/2, ZEB1/2, and HMGA2, which repress the expression of epithelial cell adhesion proteins and induce the expression of mesenchymal proteins. These changes promote the loss of cell polarity and cell-cell contacts and lead to the acquisition of a migratory, invasive phenotype that may allow cancer cell dissemination.
Promotes the Epithelial-to-Mesenchymal Transition
S phasegenes
S phasegenes
p15, p16, p21
G1 ARREST
E2F DP
DP
Rb
bHLHTranscription FactorRb
G1 S
Nucleus
Ras Raf-1
p15
Cdc25a
TGF-β
TGF-βTGF-β
TGF-β
TGF-β
TGF-β
MEK1/2
ERK1/2E2F
E2FRb
IdId2
Id2
Rb
SOSShc
GRB2
Growth Factor
CDK4/6
Cyclin D
CDK2Cyclin E
p21 or p57
DP Maxc-Myc
p15p21 Cell
Proliferation�
Miz-1
c-Myc
TGF-β
4EBP1
TRANSLATION INITIATION
eIF4E
Met-tRNA-elF2-GTP Complex
mRNA
40S ribosome subunit
TGF-β1CELEBRATING
1985–201530 YEARS
This illustration represents general processes suggested in the scienti� c literature and is not to be considered comprehensive nor de� nitive. ©2011, 2015 R&D Systems
TGF-β Signaling Regulates the Expression of Multiple Target Geneswith Tumor-Suppressing and Tumor-Promoting Effects
Global [email protected] [email protected] America TEL 800 343 7475Europe | Middle East | Africa TEL +44 (0)1235 529449China [email protected] TEL +86 (21) 52380373Rest of World bio-techne.com/fi nd-us/distributors TEL +1 612 379 2956 bio-techne.com
LEARN MORErndsystems.com/TGFbeta
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