Transcript Cell transformation

Cell transformation
Mechanisms of effect of oncogenes
and tumor suppressor genes (n.130)
Plan of seminary
• A short repeating of the topic
• Oncogenes/Protooncogenes/Oncosupress
ors
• Viruses and tumors
• The easy task
Cell transformation
Metamorphosis of a normal cell to cancer
cell
• It is irreversibile
• Gradual/multistep
Comparision of a normal and a
cancer cell
Normal cell
• A limited potential to
dividing
Cancer cell
• An immortality
• A loss of contact inhibition
• A contact inhibition
• An independence on
surrounding
• Great dependence on
other cells
• A changes in surfaces
molecules and chromosomes
!!! A cancer cells does not
divide more quickly than a
normal cell, but continually
!!!
• A resistance to apoptosis
Tumor
• Benign – a solid structure, formed by cancer cells and normal cells
stroma), in principle clear localization, can be removed
• Malignant – spreading of cancer cells to body (metastasis), mostly
beginning of cancer
Types of tumors
• Carcinomes
85%
epitheliums
Sarkomas
2%
connectivum tissues
Lymfomas
5%
spleen, nods
Leukemias
leukocytes
3%
DNA modifications - mutations
• Induced mutations (induced by mutagenes), spontaneus
mutations
• There is a relationship between mutations and cell
transfromation
• The types of mutations
• The sources of mutations
Mutagenes
• Physical: UV radiation, X rays, gama radiation
(leukaemia, skin cancer)
• Chemical: Substances interacting with DNA,
able to mutate this
• Biological: viruses, other parasites (cervix,
hepatocarcinom)
Protooncogene/Oncogene
Protooncogene – original protein
Oncogene – altered protein
Oncogenes/Oncosupresors
Oncogene – protein
with altered function
or level of
expression. It´s
dominant - one
chanched allele can
caused
transformation
Onkosupressor =
antioncogene –
protein, that prevents
transformation. It´s
recesive – both alleles
has to be damaged.
The point mutation of Ras can cause
its continuous activation
Point mutatin in the binding
domain for GTP. It can not
be cleaved – it´s
continuously activated
Loss of extracellular
regulatory domains causes
continuous activation of
receptor tyrosine kinases
Some aminoacids can be
phosphorylated and it leads to inhibition
of the protein. If the aa is mutated,
oncogen is created
Signalling pathways and proteins,
that can be altered
Ras protein
Src protein
MAPKK
Myc, Fos Jun
Raf
protein
Receptor
kinases
Growth
factors
P53,
pRb
Bcl-2
Groove factors:
v-sis: c-sis = gene for B
chain of PDGF
hst-1: gene for FGF-4
autocrine stimulation
Receptor tyrosinkinases:
v-erbB = EGFR gene
erhytroblasts, fibroblasts,
v-fms: = M-CSFR gene
met: HGFR gene
trkA: NGFR gene
Serin-threoninkinases:
Raf gene
Non receptor
tyrosinkinases:
v-abl: gene for non
receptor tyrosinkinases
Abl
v-src, v-mos
G proteins:
v-Hras, v-Kras,
Nras
Transcription factors:
v-fos,
v-myc
v-myb
v-jun
13
Tumor supressor genes (antioncogenes)
• p53 gene
• pRb gene
• proteins involved in DNA
reparation
14
Rb
Rb is fosforylated by complex of G1 cdk/cyclin.
After that it is released from E2F protein. E2F
then induces a expression of S – phase
proteins. Mutations of Rb lead to continual
activation of E2F.
p53
Human Li-Fraumeni Syndrome
(rare inherited cancer;
heterozygous p53 mutation)
p53 blocks a cell cycle at G1 phase
(by production of p21). Impaired DNA
can be repaired. If the damage is to
serious and there is no possibility to
repair it, p53 induce production of
Bax protein and it activates a
mitochondrial pathway of apoptosis.
Viruses and tumors
17
Papilomaviruses
Protein E6
–degradation p53
–interaction with Bak (inhibition of apoptosis)
– activation of telomerases
Protein E7
–Inhibition of Rb protein
–Inactivation of p21Cip and p27Kip
A) Viral oncogenes, that have no model in infected cells
Hepadnaviruses
• In 20% cases hepatitis B goes to chronical phase
• The hepatocelular carcinoma can be developed in
decades
• The development of tumor is associated with abnormal
loss of hepatocytes in 95% of cases. They are removed
by immune system due to infection by the virus.
• The damaged liver tissue recover and so permanently
proliferating hepatocytes gain mutations that lead to cell
transformation.
Herpesviruses
Epstein-Barr virus - HHV4 (EBV) – Burkitt ´s lymfom
– South - east Africa - EBV + other factors - malaria,
imunosupression etc
– Very often there is translocation of gene of primary response
– gene, myc, next to the gene for antibodies. In result, fused
gene is created and deregulation of cell signallization follows
– Moreover, herpesviruses are infectious agents causing
nasofaryngal carcinoma, Kaposi ´sarkoma and aothers
infectious diseases
B) Herpesviral oncogenes – oncogenes, that have model gene
in cell proteins, they were incorporated into the viral genom
many thousands years ago
Cyclin/CKI
pathways
vCYC
X
RB
p53
X
LANA
vIL-6
vIRF
c-myc
X
X
v Bcl-2
vFLIP
Control of
Cell Cycle
Progression
Induction of
Apoptosis
Antman & Chang. N. Engl. J. Med. 342:1027, 2000.
Retroviruses and tumors
• C) Viral oncogenes of acute oncoviruses – cellular protooncogenes,
that are incorporated into viral genom de novo during infection, this
deactivates the virus, they do not cause any know disease
• Retroviruses can incorporated into cellular genom (it is the same in 5% in
hepatocallular carcionma induced by hepadnaviruses), cellular protooncogene
is then expressed from viral promotor
deregulation, very rare
• Tumors can be induced by protein Tax (viral oncogene without cellular
template) of virus HTLV-1, too
Japan 10% infected, 0,1% leucemia, very long incubation period – to 35 years
Task
Classify the terms in bold from this
presentation into following groups:
Oncogenes
Oncosupressors
Protooncogenes
The others