Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group
description
Transcript of Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group
![Page 1: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/1.jpg)
Oncogenes &
tumour suppressors
Bart VanhaesebroeckCell Signalling Group
![Page 2: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/2.jpg)
cell signalling
regulates
every aspect of a cell’s life & death
cancer is a consequence
of deregulated cell signalling
![Page 3: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/3.jpg)
growth factor
growth factor receptor
effector region(often a tyrosine kinase) intracellular transducers
create 2nd messengers
transcription factors
DNA
mRNA
proteins
examples:cell cycle controlDNA repairanti-apoptosis
NUCLEUS
transcription
death (apoptosis)
proliferation (cell cycle progression)
growthmetabolism
migrationdifferentiationsurvival
CYTOPLASM
![Page 4: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/4.jpg)
growth factor eg. epidermal growth factor (EGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often a tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
![Page 5: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/5.jpg)
normal cell signalling is deregulated in cancer
this deregulation can occur by
• mutation
• gene amplification
• gene translocation
• gene conversion
• …
![Page 6: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/6.jpg)
cancer is a disease of DNA (1)
chromosomes of a normal cell
![Page 7: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/7.jpg)
cancer is a disease of DNA (2)
chromosomes of a cancer cell
![Page 8: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/8.jpg)
this deregulation can occur in
oncogenes
- genes capable of inducing one or more characteristics of cancer cells
- dominant gain-of-function: dominant in genetic terms: have an effect
even if only one of the 2 cellular copies of the gene is altered
- the normal versions of the genes are called ‘proto-oncogenes’
tumour suppressor genes
- genes that inhibit tumour development = ‘brakes’
- recessive loss-of-function: recessive in genetic terms: both copies of the
gene need to be inactivated (this is the ‘classical’ theory – emerging evidence
suggests that this may not be true for all tumour suppressor genes, some (like PTEN;
see later) are ‘haplo-insufficient’, and already ‘cause trouble’ if one copy is lost).
normal cell signalling is de-regulated in cancer
![Page 9: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/9.jpg)
growth factor eg. vascular endothelial growth factor (VEGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
![Page 10: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/10.jpg)
Avastin TM (Genentech)
- blocks action of VEGF, key molecule in angiogenesis
- approved by the FDA in combination with chemotherapy (intravenous 5-fluorouracil [5-FU]-
based chemotherapy) for treatment of people diagnosed with metastatic colorectal cancer
for the first time
growth factor eg. vascular endothelial growth factor (VEGF)
![Page 11: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/11.jpg)
examples of oncogenes
Tyrosine kinases: EGF-Receptor family members, BcrAbl
Intracellular signalling protein: Ras
transcription factor: Myc
anti-apoptotic protein: Bcl2
![Page 12: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/12.jpg)
growth factor eg. vascular endothelial growth factor (VEGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
![Page 13: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/13.jpg)
oncogenes
EGF-Receptor family members
overexpressed & constitutively active in breast cancer
target for (1) antibody therapy:
eg. Herceptin (Genentech) = monoclonal antibody that binds the
extracellular domain of the EGF-R family member
HER2
inhibits the growth of cells that overexpress this EGF-R
(2) tyrosine kinase inhibitor therapy:
eg. IRESSA (Astra Zeneca) = small molecule that inhibits the activity
of the intracellular kinase domain of the EGF-R
![Page 14: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/14.jpg)
resting normal cell
= hormone orgrowth factor
receptor
cell membrane
nucleus
(courtesy of Dr. Rob Stein)
![Page 15: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/15.jpg)
gene activation
stimulated normal cell
cellsurvival& division
(courtesy of Dr. Rob Stein)
![Page 16: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/16.jpg)
cancer cell
cell survival& division
gene activation
spontaneous receptordimerisation & activation
(courtesy of Dr. Rob Stein)
![Page 17: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/17.jpg)
effect of = inhibitor of receptor kinase activity
(courtesy of Dr. Rob Stein)
growthinhibition& cell death
![Page 18: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/18.jpg)
deregulated signalling proteins
are increasingly used for ’targeted therapies’
tumours seem to critically depend
on some of these pathways : ‘Achilles heels’
![Page 19: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/19.jpg)
examples of oncogenes (cont’d)
Tyrosine kinases (cont’d)
BcrAbl
Philadelphia chromosome translocation = t(9;22) : fuses
* part of the bcr gene from chromosome 22
with
* part of the abl tyrosine kinase gene on chromosome 9
creates the BcrAbl fusion protein in which the Abl tyrosine kinase
(1) has kinase activity
(2) localised throughout the cells (not only in the nucleus as in normal cells)
phosphorylation of substrates that proliferation & protect from apoptosis
in chronic myelocytic leukemia (CML)
target for Gleevec (Novartis) = tyrosine kinase inhibitor almost 100% remission in
chronic phase of disease (but resistance appears to develop).
![Page 20: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/20.jpg)
growth factor eg. epidermal growth factor (EGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
![Page 21: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/21.jpg)
examples of oncogenes (cont’d)
Ras = intracellular signalling protein
small GTPase
controls MAP kinase protein cascade important for proliferation & gene induction
mutated & constitutively active in many cancers
Myc = transcription factor - in Burkitt lymphoma
due to Epstein-Barr Virus (EBV): virus carried by >90% of the world's population – in
severely immune-suppressed patients EBV immune surveillance B-cell lymphomas
How does Myc become activated?
translocation of c-myc proto-oncogene into or near one of the immunoglobulin loci
found in almost every case of Burkitt’s B-cell lymphoma in man
(see lecture D. Linch & A. Khwaja)
![Page 22: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/22.jpg)
examples of oncogenes (cont’d)
Bcl2 = anti-apoptotic protein = B-cell leukemia-2 (see lecture notes D. Linch & A. Khwaja)
protects against cell death
was the first ‘oncogene’ discovered which does not regulate proliferation
initially identified as a translocation breakpoint common in many B-cell lymphomas
as a result of this translocation, the bcl-2 gene comes under the control of the
immunoglobulin heavy chain enhancer & is constitutively expressed in B-cells
the resulting protection from apoptosis apparently permits the survival &
accumulation of aberrant B-cells that ultimately give rise to lymphoid malignancies
![Page 23: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/23.jpg)
examples of tumour suppressor genes
gene regulator: Rb
transcription factor: p53
lipid phosphatase: PTEN
![Page 24: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/24.jpg)
tumour suppressor genes
- genes that inhibit tumour development
- classical theory: recessive (in genetic terms): both gene copies in the cell need to be
inactivated before cancer can arise
almost all genes in our cells are present in 2 redundant copies (one from mother & one
from father): if one copy is lost, the other copy serves as a backup. In the case of
tumour suppressor genes, this offers a measure of protection.
loss-of-heterozygosity = LOH = loss of the 2nd allele of a tumour suppressor (by
gene conversion, mutation, gene deletion etc)
some people carry an inactivating mutation in a tumour suppressor gene in their
sperm or eggs
offspring is more prone to lose the 2nd allele (eg. by a so-called ‘sporadic’ mutation)
predisposition to cancer. eg. familial retinoblastoma : carry mutations in Rb gene
(see also lecture notes Dr. Daniel Hochhauser)
![Page 25: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/25.jpg)
growth factor eg. epidermal growth factor (EGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
![Page 26: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/26.jpg)
first identified in the rare eye tumour retinoblastoma (occurs only up to the age of 6-7)
- arises from retinoblasts: cells in the embryonic retina
that will become photoreceptors
- ‘sporadic’ form: afflicted children have no close relatives who
have previously contracted this cancer ( familial form)
Rb = retinoblastoma
Alfred Knutson theory (based on epidemiological studies):
> sporadic form: the 2 mutations occur one after another (either during
embryonic development of shortly after birth), in one of the cells of the retina
extremely rare & occurs slighly later in life (mean age: 30 months)
children mostly carry a single retinal tumour in one eye
> familial form: all cells of the embryo carry 1 mutated allele of the Rb gene
(including all cells of the retina).
chance of loss of 2nd allele (LOH)
frequency of retinoblastoma & occurs early (mean age: 14 months)
often multiple tumours in both eyes
![Page 27: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/27.jpg)
Rb = retinoblastoma protein
‘pocket’ protein: binds & inhibits E2F transcription factors
‘super’ phosphorylation of Rb (by cyclin-dependent kinases that act in cell cycle)
release of E2F from the DNA brake is gone allows transcription of genes
important for cell cycle progression
RBE2F
G1
P
RB
E2F
S
P PP
cyclin Ec-Mycother
phosphatases
RBE2F
G1
PcyclinD/CDK4
in normal cell:
in Rb -/- cell: loss-of-expression of Rb brake is lost no brakes on cell cycle progression
![Page 28: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/28.jpg)
examples of tumour suppressor genes (cont’d)
p53
= transcription factor
in 50% of tumours: lost or (in most cases) mutated such that it can no longer bind DNA
= ‘GUARDIAN OF GENOME’: ‘senses’ DNA damage, stress
if damage is moderate: stalls cells in cell cycle until DNA is repaired
if damage is severe: induces cell death programme
cell cycle arrest
STRESS(irradiation, hypoxia, anoxia, …)
p53
cell death
![Page 29: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/29.jpg)
examples of tumour suppressor genes (cont’d)
p53 (cont’d):
Not entirely clear how p53 works, but a very plausible pathway goes as follows:
damage of cellular DNA activation of ATM / DNA-PK (DNA-dependent protein
kinase) phosphorylation of p53 increased p53 stability p53 accumulation &
activation induction of
* cell cycle inhibitors (such as p21)
* apoptosis-inducing proteins (such as Bax, Fas-receptor, ..)
* IGF-BP3 (a secreted binding protein for the survival factor IGF-1)
EXPRESSION OF THESE NEGATIVE REGULATORS IS LOST UPON LOSS OF p53
![Page 30: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/30.jpg)
example of a dose-dependent tumour suppressor gene: PTEN
![Page 31: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/31.jpg)
protein kinases
PDK1, Akt/PKB, Btk, Itk, …
adaptor proteins
Gab1, Bam32, DAPP1, …
GEFs / GAPs for small GTPases
of Rac, Ras, Arf families
cytosol
PIP2
PI3K PIP3
+
signalling by PI 3-kinases
cancer
inflammation
diabetes
DISEASE:
proliferation
survival
growth
differentiation
migration
CELLS:
ras
PI3K
receptor Akt
deregulation of PI3K signalling in cancer
![Page 32: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/32.jpg)
PI3K PIP3
PIP2
PTEN = lipid phosphatase
deregulation of PI3K signalling in cancer (cont’d)
by loss of function of the PTEN tumour suppressor gene
PTEN +/- mice:
develop cancerwith 100% penetrance
in many
sporadic cancers
e.g. glioblastoma,
endometrium, …
germline PTEN mutations
in some hamartoma
syndromes
e.g. Cowden syndrome
: when inactivated PI3K pathways ‘on’
under those conditions, the wild-type PTEN allele is retained, and only the dose of PTEN
enzyme is altered
Apparently, lowering the dose of a tumour suppressor gene can already have dire
effects for cancer development, and it is thus not always necessary to lose BOTH copies
of a tumour suppressor gene !!! (( Knutson theory)
![Page 33: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/33.jpg)
growth factor eg. epidermal growth factor (EGF)
growth factor receptor eg. EGF-receptor (EGF-R)
effector region(often tyrosine kinase) intracellular transducers
create 2nd messengerseg. - Ras - protein kinases (Tyr, Ser, Thr)
transcription factors eg. Myc, p53
DNA
mRNA
proteins
examples:cell cycle control : Rb, p16, CDKsDNA repair : ATManti-apoptosis : Bcl2, Bad
NUCLEUS
transcription
summary: oncogenes and tumour suppressor genes can alter every step of cellular signalling
![Page 34: Oncogenes & tumour suppressors Bart Vanhaesebroeck Cell Signalling Group](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815a22550346895dc765a7/html5/thumbnails/34.jpg)
THE END
(thank you for your attention)