gene transcription

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Gene Transcription G 0 G 1 Primi ng S G 2 M Cell Cell Cycle Growth Factors + + Growth Factors & Cell Cycle Receptors

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Gene Transcription. S. Growth Factors. +. Priming. G 1. G 0. G 2. Cell Cycle. M. Growth Factors & Cell Cycle. Receptors. ATP. ATP. TK. TK. +. EGFR Function in Normal Cell. Gene Transcription Cell Cycle Progression. Antiapoptosis. Cell Proliferation. Angiogenesis. TK. TK. - PowerPoint PPT Presentation

TRANSCRIPT

Page 1: Gene Transcription

Gene Transcription

G0G1

Priming

S

G2

M

Cell Cell Cycle

Growth Factors

++

Growth Factors & Cell Cycle

Receptors

Page 2: Gene Transcription
Page 3: Gene Transcription
Page 4: Gene Transcription
Page 5: Gene Transcription
Page 6: Gene Transcription
Page 7: Gene Transcription
Page 8: Gene Transcription

TK

EGFR Function in Normal Cell

TKATP ATP

Cell Proliferation Antiapoptosis

Angiogenesis

Gene Transcription

Cell Cycle Progression

+

Page 9: Gene Transcription

TKTK

EGFR signal transduction in tumour cells

Survival(anti-apoptosis)

PI3-K

STAT3AKTPTEN

MEK

Gene transcriptionMAPK

Proliferation/maturation

Chemotherapy /radiotherapyresistance

Angiogenesis Metastasis

pYpY

RAS RAFSOS

GRB2pY

G1

SM

G2

Page 10: Gene Transcription

Normal CellCancerous CellUp Regulation

Mutation

Consequence of proliferation of EGFR receptors

Page 11: Gene Transcription

TK TK TK TK

Strategies to inhibit EGFR signaling

-- -- -- --

EGFR tyrosine kinase inhibitors Anti-EGFR mAbs

Anti-ligand mAbs Bispecific

Abs

Imm

une effector cell

ATP

Page 12: Gene Transcription

The PDGF-Receptor tyrosine kinase can bind several SH2-domaincontaining proteins simultaneously.

716Tyr-P

1009Tyr-P

763Tyr-P

740Tyr-P

1021Tyr-P

771Tyr-P

Grb2PI,3 kinaseGAP

Shp2

{

{STAT

Shc/Src

1043Tyr-P PLC-

Ligand Binding

KinaseDomain

Page 13: Gene Transcription

The MAP Kinase (Extracellular-Related Kinase ERK) Cascade

Mitogens, Growth Factors

Ras

RAF

MAPK

MAPKK/MEK1

MAPKKK

MAP4K

MAP3K

MAP2K

MAPK

GTPase

Transcriptional Regulation

Cytokines, Cell Stress

Rac, Cdc42

MEKK1

PAK

JNKK/SEK

JNK

}Cytosol

Nucleus

Page 14: Gene Transcription

Raf

Page 15: Gene Transcription

Background Information

What is PDGF?

It is also known as platelet-derived growth factor.

There are four types of ligands: PDGFA, B, C, and D.

PDGF ligands are homodimers.

Page 16: Gene Transcription

If there are PDGF, there must be PDGFRs

Three types of receptors: PDGFR alpha alpha, alpha beta, and beta beta.

Page 17: Gene Transcription

PDGFRB’s Functions in Cellular Level

Receptor tyrosine kinase.

Ligand binding-> dimerization-> autophosphorylation.

Activates the Ras-MAPK, PI3K, & phospholipase C gamma pathways.

Page 18: Gene Transcription

PDGFR Activation Pathways

Hoch & Soriano (2003) Development 130:4772

Page 19: Gene Transcription

What does PDGFRB do for the organism?

PDGFR + PDGF regulate development of vascular smooth muscle cells

Mice lacking PDGF or PDGFR die perinatally with extensive hemorrhaging.

Page 20: Gene Transcription
Page 21: Gene Transcription