Cancer synthesis
Hallmarks of cancer
1. Proto-oncogenes >> give cells a proliferative advantage
2. Tumor suppressor genes >> often deregulated in cancer. Is there to restrict cell division
3. Caretaker genes >> protect the integrity of the genome
Cell proliferation >> deregulated cell proliferation
Cell death >> suppressed cell death
Conversion of proto-oncogenes into oncogenes
- Almost all oncogenes are derived from cellular genes (proto-oncogenes) whose wt-products
promote for example cell proliferation.
- Gain of function mutation
o Point mutation
o Chromosomal translocation >> different chromosomes are glued together
If the break points occur in a gene>> at the break point the genes get fused,
you’ll get a new protein with new functions in the cell.
Normal gene is taken out of its normal regulatory region. Can move into
another (more active) chromosome. A gene that should be silenced can be
suddenly activated.
o Chromosomal translocation >> different promoter usage, inappropriate expression.
o Amplification of DNA segment >> overproduction of encoded protein
- Dominant, one mutaded gene allele induces cancer.
Proteins
1. Intracellular proteins regulating cell cycle progression
2. Receptors or signal transducers for secreted hormones that inhigbit cell cycle progression
3. Checkpoint-control proteins that arrest the cell cycle upon DNA damage
4. Apoptosis-promoting proteins
5. DNA-repair enzymes, encoded by caretaker genes.
Usually, tumour suppressive genes are recessive.
Hallmarks of cancer
Sustaining proliferative signalling
A cancer cell needs to get signals that they need to proliferate
- Some tumour cells can make their own growth factors
- Stimulate normal cells to produce necessary growth factors
- Elevating levels of receptor proteins
- Constitutive activation of downstream components
They discovered it by isolating DNA from cancer cells and injecting this DNA into the fiber blasts.
- Oncogenic transformation
- Cells continue growing.
- Which gene or which pieces of DNA were involved?
o Ras protein/gene
Signalling protein
When a cell gets activated (by a growth factor) the final proteins can change
the characteristics of the cell
Ras is an intermediate>> uses its GTP activity. Binds GTP in order to activate.
Ras has GTPase activity (remove phosphate) and convert triphosphate to
diphosphate. When the protein is changed into a diphosphate, the protein is
no longer active.
To keep Ras active, impair the activity of GTPase. Then Ras stays active.
o rasD >> is a genetically dominant mutant version of the cellular ras gene.
, The oncogene: hydrolyzes bound GTP very slowly and therefore accumulates
in the active state (sending prolonged growth-promoting signals to the
nucleus)
o You can also affect a phosphatase: PTEN
If you mutate PTEN, then the active phosphorylating molecule can no longer
be phosphorylated and remain active.
Evading growth suppressors
Cancer cells must circumvent progras that negatively regulate cell proliferation
- Cells passing through the restriction point: irreversibly committed to enter S-phase and
replicate
- Important control systems to regulate the restriction point: like cyclin-dependent kinases
(CDKs) and RB protein.
Restriction point can be mutated:
- CycD-CDK4 activates phosphorylation activity pointing towards Rb, phosphorylates E2F.
- E2F is a transcription factor for genes that drive the cell cycle
- If Rb is phosphorylated, it can no longer bind to E2F >> cell goes past the restriction point.
- P16 is an inhibitor of this phosphorylation complex. P16 needs to be released from the
complex in order to start its kinase activity.
o If you want to mutate: hijack this system
1. Cyclin D1: elevating the levels,
Total pool of cyclin D1 levels is increased, so you will get enhanced
phosphorylation activity to Rb
2. Translocation
Tumour s of antibody producing B lympohocytes
Cyclin D gets signals that it should be highly transcribed
3. Loss of function mutations of p16
Epigenetic regulation
P16 promoter can be methylated, as a result transcription factors cannot
bind, thus the gene is no longer transcribed.
4. Retinoblastoma itself
Eye cancer
Inactivation of Rb. Main function that is affected is its binding to E2F. then Rb
will no longer inhibit E2F, and E2F can act.
Binding of the inhibitory E7 protein (designed to bind to Rb) of HPV. By
binding of E7 to Rb, it will make Rb unable to bind to Rb.
Resisting of cell death
A cell has a program that tells it to die.
During tumorigenesis cancer cells experience many physiological stresses.
- The apoptotic trigger is controlled by the BDL-2 family of proteins.
- DNA damage sensoring via TP53: Noxa and Puma upregulation
- P53: mutated
- Overexpress BCL-2
P53: central protein, converts different stress signals, can act as a transcription factor, decide what
the cell should do (apoptosis, DNA repair, differentiation, senescence, cell growth arrest).
- Commonly mutated in cancer.
- P53 is a transcription factor
o Has certain domains that are frequently mutated,
Hallmarks of cancer
1. Proto-oncogenes >> give cells a proliferative advantage
2. Tumor suppressor genes >> often deregulated in cancer. Is there to restrict cell division
3. Caretaker genes >> protect the integrity of the genome
Cell proliferation >> deregulated cell proliferation
Cell death >> suppressed cell death
Conversion of proto-oncogenes into oncogenes
- Almost all oncogenes are derived from cellular genes (proto-oncogenes) whose wt-products
promote for example cell proliferation.
- Gain of function mutation
o Point mutation
o Chromosomal translocation >> different chromosomes are glued together
If the break points occur in a gene>> at the break point the genes get fused,
you’ll get a new protein with new functions in the cell.
Normal gene is taken out of its normal regulatory region. Can move into
another (more active) chromosome. A gene that should be silenced can be
suddenly activated.
o Chromosomal translocation >> different promoter usage, inappropriate expression.
o Amplification of DNA segment >> overproduction of encoded protein
- Dominant, one mutaded gene allele induces cancer.
Proteins
1. Intracellular proteins regulating cell cycle progression
2. Receptors or signal transducers for secreted hormones that inhigbit cell cycle progression
3. Checkpoint-control proteins that arrest the cell cycle upon DNA damage
4. Apoptosis-promoting proteins
5. DNA-repair enzymes, encoded by caretaker genes.
Usually, tumour suppressive genes are recessive.
Hallmarks of cancer
Sustaining proliferative signalling
A cancer cell needs to get signals that they need to proliferate
- Some tumour cells can make their own growth factors
- Stimulate normal cells to produce necessary growth factors
- Elevating levels of receptor proteins
- Constitutive activation of downstream components
They discovered it by isolating DNA from cancer cells and injecting this DNA into the fiber blasts.
- Oncogenic transformation
- Cells continue growing.
- Which gene or which pieces of DNA were involved?
o Ras protein/gene
Signalling protein
When a cell gets activated (by a growth factor) the final proteins can change
the characteristics of the cell
Ras is an intermediate>> uses its GTP activity. Binds GTP in order to activate.
Ras has GTPase activity (remove phosphate) and convert triphosphate to
diphosphate. When the protein is changed into a diphosphate, the protein is
no longer active.
To keep Ras active, impair the activity of GTPase. Then Ras stays active.
o rasD >> is a genetically dominant mutant version of the cellular ras gene.
, The oncogene: hydrolyzes bound GTP very slowly and therefore accumulates
in the active state (sending prolonged growth-promoting signals to the
nucleus)
o You can also affect a phosphatase: PTEN
If you mutate PTEN, then the active phosphorylating molecule can no longer
be phosphorylated and remain active.
Evading growth suppressors
Cancer cells must circumvent progras that negatively regulate cell proliferation
- Cells passing through the restriction point: irreversibly committed to enter S-phase and
replicate
- Important control systems to regulate the restriction point: like cyclin-dependent kinases
(CDKs) and RB protein.
Restriction point can be mutated:
- CycD-CDK4 activates phosphorylation activity pointing towards Rb, phosphorylates E2F.
- E2F is a transcription factor for genes that drive the cell cycle
- If Rb is phosphorylated, it can no longer bind to E2F >> cell goes past the restriction point.
- P16 is an inhibitor of this phosphorylation complex. P16 needs to be released from the
complex in order to start its kinase activity.
o If you want to mutate: hijack this system
1. Cyclin D1: elevating the levels,
Total pool of cyclin D1 levels is increased, so you will get enhanced
phosphorylation activity to Rb
2. Translocation
Tumour s of antibody producing B lympohocytes
Cyclin D gets signals that it should be highly transcribed
3. Loss of function mutations of p16
Epigenetic regulation
P16 promoter can be methylated, as a result transcription factors cannot
bind, thus the gene is no longer transcribed.
4. Retinoblastoma itself
Eye cancer
Inactivation of Rb. Main function that is affected is its binding to E2F. then Rb
will no longer inhibit E2F, and E2F can act.
Binding of the inhibitory E7 protein (designed to bind to Rb) of HPV. By
binding of E7 to Rb, it will make Rb unable to bind to Rb.
Resisting of cell death
A cell has a program that tells it to die.
During tumorigenesis cancer cells experience many physiological stresses.
- The apoptotic trigger is controlled by the BDL-2 family of proteins.
- DNA damage sensoring via TP53: Noxa and Puma upregulation
- P53: mutated
- Overexpress BCL-2
P53: central protein, converts different stress signals, can act as a transcription factor, decide what
the cell should do (apoptosis, DNA repair, differentiation, senescence, cell growth arrest).
- Commonly mutated in cancer.
- P53 is a transcription factor
o Has certain domains that are frequently mutated,
