Transcript Cell transformation

Cell transformation
Mechanisms of effect of oncogenes
and tumor suppressor genes
Plan of seminar
• A short introduction to 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
• A contact inhibition
• Great dependence on
other cells
!!! A cancer cells does not
divide more quickly than a
normal cell, but continually
!!!
Cancer cell
• An immortality (see HeLa
cells)
• A loss of contact inhibition
• An independence on
surrounding
• A changes in surfaces
molecules and chromosomes
• A resistance to apoptosis
Tumor
• Benign - a solid structure, formed by cancer cells and normal cells
(stroma), in principle compact localization, can be removed
• Malignant - spreading of cancer cells to body (metastasis), mostly
beginning of cancer
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
Mutagenes
• Physical: UV radiation, X rays, gama radiation
(leukaemia, skin cancer)
• Chemical: Substances interacting with DNA,
capable of mutate this
• Biological: viruses, other parasites (cervical
cancer, hepatocelular carcinoma)
Protooncogene/Oncogene
Protooncogene - original protein
Oncogene - altered protein
Oncoproteins/Oncosupresors
Oncoprotein - protein
with altered function or
level of expression
inducing cell
transformation. The
heredity is dominant one chanched allele
can cause
transformation in all
daughter cells.
Onkosupressor =
antioncogene - protein,
that prevents
transformation. The
heredity is recesive - both
alleles has to be
damaged not to protect
the daughter cells against
transformation.
The point mutation of Ras can cause
its continuous activation
Point mutatin in the GTPcleavage domain. GTP can
not be cleaved - it is
continuously activated
Loss of extracellular
regulatory domains causes
continuous activation of
receptor tyrosine kinases
Moreover, some aminoacids can be
phosphorylated and it leads to inhibition
of the protein. If the aa is mutated,
oncogen is created.
Signaling 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
v-hst-1: c-hst = gene for FGF-4
autocrine stimulation
Receptor tyrosinkinases:
v-erbB: c-erb = EGFR gene
erhytroblasts, fibroblasts,
v-fms:c-fms = M-CSFR gene
met: c-met = HGFR gene
trkA: c-trkA = NGFR gene
Serin-threoninkinases:
v-Raf: c-Raf gene
Non receptor tyrosinkinases:
v-abl: c-abl,
v-src: c-src,
v-mos: c-mos
G proteins:
v-Hras: c-Hras,
v-Kras: c-Kras
N-ras: c-Nras
Transcription factors:
v-fos: c-fos
v-myc: c-myc
v-myb: c-myb
v-jun: c-jun
The list of protooncogenes from
previous slide
12
Tumor supressor genes (antioncogenes)
• p53 gene
• pRb gene
• genes for proteins involved
in DNA reparation
13
pRb
Rb is fosforylated by complex of G1 cdk/cyclin.
Subsequently 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
16
HCV
• Chronical persistent infection observed in adult immunocompetent
patient (70 – 85% pacientů) it can lead to hepatocelular carcinoma
by the same mechanisms like HBV
• Transmission: by blood - nonsterile injection needles, blood
transfusion, drug users, sexual?
• Treatment: Interferon a, ribavirin (20 - 30%, toxic)
• 130 000 000 HCV positive persons: 0,1% (UK) - 20% (Egypt)
Pakistan (4.8%) and China (3.2%), more than 350 000 people die from
HCV-related liver diseases each year
• Vakcinace: there is no vaccination
• Prevention: control of blood and blood derivates, disposable sterile
needles
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.
• There are 350 mil. HBV infected worldwide
• Transmission by blood, throught injections (drugs, tatoo, hospitals) and
sexual
• There is commonly used hexavaccine or combined vaccines against HBV
nad HAV
Papilomaviruses
• More than 100 species (about 40 was sexual transfer described, cca
15 have oncogenical potential)
• Strongly species - specific, infection of skin and mucous membrane
where can induce formation of tumors
• Most common sexual transmitted infection (to 80% humans infected
during the life)
• Most common cause of world-wide incidence of cervical carcinoma
are HPV types 16 (53-70 %) and 18 (13-26 %)
• Cervical carcinoma is caused by HPV 16 a 18 in approximately
0,1% infected women
• World-wide 500,000 new cases a year, 275,000 humans die a year.
Usually suppressed by immune system, no tumor is formed,
chronical infections are high risk, e. g. Viral genom can be integrated
• Typical cancer cells produced E6 and E7
Oncogenes of 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
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 and others
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 also induced by protein Tax (viral oncogene without cellular
template) of virus HTLV-1
Japan 10% infected, Jews in Ethiopia, 0,1% leucemia, very long incubation period - to
35 years, HTLV - 1, HTLV -2, transmission like HIV virus, 15 –25 milionů infict. HTLV -1
Task
Classify the terms in bold from this
presentation into following groups:
Oncogenes
Oncosupressors
Protooncogenes
The others