Cell transformation

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Cell transformation

• Mechanisms of effect of oncogenes and tumor
  suppressor genes

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Plan of seminar

• A short introduction to 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

• 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

• 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 !!!
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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

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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 - mutagenes

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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)

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Protooncogene/Oncogene
Protooncogene - original protein
Oncogene - altered protein
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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.
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Loss of extracellular regulatory domains causes
continuous activation of receptor tyrosine
kinases
The point mutation of Ras can cause its
continuous activation
Point mutatin in the GTP- cleavage domain. GTP
can not be cleaved - it is continuously activated
Moreover, 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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Signaling pathways and proteins, that can be
altered
P53, pRb
Bcl-2
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• 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-fmsc-fms M-CSFR gene
• met c-met HGFR gene
• trkA c-trkA NGFR 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
Serin-threoninkinases v-Raf c-Raf gene
The list of protooncogenes from previous slide
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• Tumor supressor genes (antioncogenes)

• p53 gene
• pRb gene
• genes for proteins involved
• in DNA reparation

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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.
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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.
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Viruses and tumors
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HCV

• Chronical persistent infection observed in adult
  immunocompetent patient (70 85 pacientu) 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

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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.
• 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

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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

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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
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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 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
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(No Transcript)
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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 milionu infict. HTLV -1

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Task

• Classify the terms in bold from this presentation
  into following groups
• Oncogenes
• Oncosupressors
• Protooncogenes
• The others