cell transformation mechanisms of effect of oncogenes and tumor suppressor genes (n.130)
TRANSCRIPT
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Cell transformation
Mechanisms of effect of oncogenes and tumor suppressor genes (n.130)
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Plan of seminary
• A short repeating of the topic
• Oncogenes/Protooncogenes/Oncosupressors
• Viruses and tumors
• The easy task
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Cell transformation
Metamorphosis of a normal cell to cancer cell
• It is irreversibile
• Gradual/multistep
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Comparision of a normal and a cancer cell
Normal cell
• A limited potential to dividing
• A contact inhibition
• Great dependence on other cells
Cancer cell
• An immortality
• A loss of contact inhibition
• An independence on surrounding
• A changes in surfaces molecules and chromosomes
• A resistance to apoptosis!!! A cancer cells does not divide more quickly than a normal cell, but continually !!!
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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
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Types of tumors
• Carcinomes 85%epitheliums
Sarkomas 2%
connectivum tissues
Lymfomas 5%spleen, nods
Leukemias 3%leukocytes
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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
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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)
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Protooncogene/Oncogene
Protooncogene – original protein Oncogene – altered protein
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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.
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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
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Signalling pathways and proteins, that can be altered
Growth factors
Receptor kinases
Src proteinRas protein Raf
protein
MAPKK Myc, Fos Jun
P53, pRb
Bcl-2
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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
13
Non receptor tyrosinkinases:
v-abl: gene for non receptor tyrosinkinases Abl
v-src, v-mos
G proteins:
v-Hras, v-Kras,
Nras
Serin-threoninkinases:
Raf gene
Transcription factors:v-fos,
v-mycv-myb
v-jun
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Tumor supressor genes (antioncogenes)
14
• p53 gene• pRb gene• proteins involved in DNA
reparation
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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.
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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.
Human Li-Fraumeni Syndrome (rare inherited cancer; heterozygous p53 mutation)
p53
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17
Viruses and tumors
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Protein E6 –degradation p53 –interaction with Bak (inhibition of apoptosis)– activation of telomerases
Protein E7–Inhibition of Rb protein–Inactivation of p21Cip and p27Kip
Papilomaviruses
A) Viral oncogenes, that have no model in infected cells
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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.
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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
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RB
Control of Cell Cycle
Progression
c-mycvIRF
Induction of Apoptosis
v Bcl-2
vFLIP
vIL-6
XX
XvCYC p53 LANAX
Cyclin/CKI pathways
Antman & Chang. N. Engl. J. Med. 342:1027, 2000.
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• 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
Retroviruses and tumors
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Task
Classify the terms in bold from this presentation into following groups:
Oncogenes
Oncosupressors
Protooncogenes
The others