tumor genes Flashcards
what are the types of cancer?
carcinoma, sarcoma, myelomas, leukemia, lymphomas, mixed types
how is cancer developed?
multistep process:
cells gradually become malignant through progressive alterations –> multiple abnormalities accumulate –> selection for grwoth advantage
what are the stages of tumor development?
tumor initiation–> tumor progression (growth advantage, survival, invasion, metastasis)
what are the causes of cancer?
carcinogens, tumor promoters
what are the characteristic properties (name 8) of cancer cells?
1.lack density dependent inhibition of proliferation
2. reduced requirements of growth factors
3.less regulated cell-cell, cell-matrix (loss of E-cadherin)
4.not sensitive to contact inhibition
5. secrete proteases and growth factors –> invasion, angiogenesis
6.dont differentiate normaly
7.do not undergo apoptosis
8.unlimited DNA replication, overexpression of telemorease
what are proto-oncogenes?
normal cell genes from which oncogenes originated
often proteins of a signal transduction pathway that controls cell proliferation –> growth factor receptors (protein-tyrosine kinases)
which signaling pathways/oncogenes play a role in cancer if they are mutated?
1.NOTCH- NICD
2. IL receptor- JAK/STAT
3. growth factor: ErbB2/HER2 receptor – RAS – either activates PI3K/Akt/mTor (inhibited by PTEN) or Raf/Mek/ERK/MAPk
4. WNT- frizzled- beta catenin-APC
what types of mutation occur in cancer?
point mutation (RAS)
abnormal chromosomes: translocation, duplications, deletions (c-myc, c-abl)
LOF in transcription factors
GOF in kinases, receptor mutations, ligand mutations
what are the properties of oncogenes?
can encode transcription factors normally induced by growth factors
proto-oncogene proteins have normal roles in growth factor stimulated signal transduction pathways
what are tumor suppressor genes?
normally they inhibit cell proliferation and tumor development
in many tumors, both genes are lost or inactivated –> contribution to an abnormal proliferation of tumor cells
how is retinoblastoma inherited?
inherited as dominat autosomal, either hereditary or sporadic
what causes retinoblastoma?
Rb1 gene encodes pRB protein
loss of pRB can lead to cancer
what is the function of pRB?
suppresses cell division in absence of mitotic signals
prevents transition from G1 to S phase
hypophosphorylated pRB: binding and inhibition of E2F –> cell cycle arrest
pRb hyperphosphorylation by CDK: release of E2F
in cancer cells disrupted pRB function results in aberrant cell proliferation
what are the types of retinoblastoma and what are their characteristics/mutations?
bilateral: both eyes –> germline mutation or sporadic
unilateral: one eye –> somatic mutation
what is the two hit model in regards to retinoblastoma?
first hit: inheritance of one defective Rb gene
second hit: only one successive genetic alteration in one of the retinal cells
tumor formation requires two genetic alterations
what is loss of heterozygosity (LOH)?
Loss of an entire chromosome by chromosome non-disjunction and recombination of the mutant allele
why are mutant tumor suppressor genes transmitted through the germline while ocogenes are usually not?
oncogene is dominant at the cellular level and disruption of normal tissue development in the embryo –> embryo dies
tumor suppressor genes are recessive at the cellular level and normal embryonic development
why can the RET oncogene be transmitted through the germline?
expression is limited to a small set of tissue, delayed expression of ret during embryogenesis
what are examples of tumor suppressor genes
pRB
p53
APC
what is p53 and what is the function of p53?
tumor suppressor
is frequently inactivated in cancer
is a transcription factor
FUNCTION:
hinders proliferation of damaged cells
prevents genome mutations
what is the interaction between oncogenes and tumor suppressors?
tumor suppressor genes inhibit regulatory pathways stimulated by products of oncogenes
which regions of p53 can be mutated?
Transactivation domain
proline rich domain
DNA binding domain (cancer hotspot mutations)
tetramerization domain
Lysine rich domain
change of conformation: the mutations are dominant negative
what is the mechanism of p53 action?
transactivation of target genes by tetratmeric p53
how is p53 controlled?
through negative feed back loops
1.active p53 if tetramers are formed
2.transactivation of various genes (mdm2)
3.production of mdm2 protein
4.mdm2 binds p53 in the nucleus–> inactivation of p53
5.export to the cytoplasm and mdm2 mediated ubiquitination of p53
6.p53 degradation
what activates p53?
activation of DNA damage sensing kinases leads to p53 stabilisation and acivation
what are the paradigms of tumor suppression?
two hit paradigm
haploinsufficiency
quasi suffiency
obligate haploinsufficiency
what is haploinsufficiency?
a single copy of a wild type allele at a locus in heterozygous combination with a mutated allele –> although wild-type allele still produces the normal product, the total product is sufficient for induction of cancer
e.g. p53
what is quasi sufficiency?
tumor suppression is impaired after subtle downregulation of expression without loss of eveb one allele
e.g. pTEN
what is obligate haploinsufficiency?
is more tumorigenic than complete loss of the TSG usually due to the activation of fail-safe mechanisms following the complete loss of TSG expression
what is the function of APC?
tumor suppressor protein
loss of APC function leads to unregulated dividing cells
is component of Wnt/frizzled signaling pathway
what are the types of mutation in APC?
germline and somatic
framehsift and nonsense mutations
c-terminally truncated protein
what are somatic mutations?
most changes in DNA usually happen during our lifetime
what are germline mutations?
inherited DNA from parents that greatly increase risk of developing certain cancer
what are driver mutations?
confer grwoth advantage on cancer cells
causally implicated in oncogenesis
what are passenger mutations?
without functional consequences for oncogenesis
no growth advantage on the cancer cell
