Biochemistry and Molecular Biology II – Lecture 11 (29-5-18): Cancer by Joost
Martens
07-08-2016:
Lecture opnieuw teruggekeken:
Conversion of a proto-oncogene into an oncogene generally involves a gain-of-
function mutation:
This can happen via:
1. Point mutation hyperactive or constitutively active (missense, nonsense,
silent)
2. Chromosomal translocation chimeric proteins constitutively active
3. Chromosomal translocation different promoter usage inappropriate
expression
4. Amplification of DNA segment overproduction of encoded protein
Gain of function mutations are often dominant one mutated gene allele already
induces cancer.
Loss-of-function mutations of tumor suppressor genes:
- Proteins that somehow inhibit cell proliferation
Loss of function mutations are genetically recessive both alleles must be
lost/inactivated!!!!
Hallmarks of cancer:
1. Sustaining proliferative signaling
2. Evading growth suppressors
Counteract tumor suppressor genes such as Rb and tp53
Hypermethylation leads to a gene becoming silent, because of the formation of
heterochromatin
3. Resisting cell death
- Elevated levels of anti-apoptosis protein BCL-2 (proto-oncogene)
- Loss of p53 normally: ATM complex phosphorylates p53 activates p21
- When MDM2 binds to p53 it targets p53 for proteasomal degradation. This
means that the tumor-suppressor function of p53 is inhibited, which makes
MDM2 an oncogene.
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
- Loss of E-cadherin E-cadherins normally regulate cell-cell interactions.
*You need multiple hits in order to get cancer accumulation of mutations.
Driver/passenger mutations:
Driver mutations: mutations that drive tumor and cancer progression.
Passenger mutations: other mutations can occur during the process of
tumorigenesis, which have no beneficial effect for the cancer.
Martens
07-08-2016:
Lecture opnieuw teruggekeken:
Conversion of a proto-oncogene into an oncogene generally involves a gain-of-
function mutation:
This can happen via:
1. Point mutation hyperactive or constitutively active (missense, nonsense,
silent)
2. Chromosomal translocation chimeric proteins constitutively active
3. Chromosomal translocation different promoter usage inappropriate
expression
4. Amplification of DNA segment overproduction of encoded protein
Gain of function mutations are often dominant one mutated gene allele already
induces cancer.
Loss-of-function mutations of tumor suppressor genes:
- Proteins that somehow inhibit cell proliferation
Loss of function mutations are genetically recessive both alleles must be
lost/inactivated!!!!
Hallmarks of cancer:
1. Sustaining proliferative signaling
2. Evading growth suppressors
Counteract tumor suppressor genes such as Rb and tp53
Hypermethylation leads to a gene becoming silent, because of the formation of
heterochromatin
3. Resisting cell death
- Elevated levels of anti-apoptosis protein BCL-2 (proto-oncogene)
- Loss of p53 normally: ATM complex phosphorylates p53 activates p21
- When MDM2 binds to p53 it targets p53 for proteasomal degradation. This
means that the tumor-suppressor function of p53 is inhibited, which makes
MDM2 an oncogene.
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
- Loss of E-cadherin E-cadherins normally regulate cell-cell interactions.
*You need multiple hits in order to get cancer accumulation of mutations.
Driver/passenger mutations:
Driver mutations: mutations that drive tumor and cancer progression.
Passenger mutations: other mutations can occur during the process of
tumorigenesis, which have no beneficial effect for the cancer.
