Neoplasia: Tumor Supressor Gene Flashcards
Tumor suppressor gene with intact oncogene
Quiescence
Permanent cell cycle arrest rather than uncontrolled proliferation
Senescence
Tumor suppressor genes activity
- Growth inhibitory pathways
- Pro-differentiation
- Mitogenic signals
Those 3 activity of TSG originates outside the cells and use
Receptors
Signal transducers
Nuclear transcription regulation
First TSG discovered
RB or retinoblastoma gene
Prototype of gene of this type
RB
Familial RB
40%
Autosomal dominant
10,000 folds
Carriers of RB
Both eyes
Develop osteosarcoma and other soft tissue sarcoma
60%
Occur sporadic
One eye only
Occurence of RB
Two hit hypothesis of oncogenesis
Pathogenesis of RB
2 mutations of RB focus on chromosome 13q14
Both RB mutation in tumor retinal cell acquired
Sporadic form
All somatic cells inherit one mutated copy of RB gene
Familial form
In familial case first hit
Inherit one defective copy of the RB gene
Second hit
Spontaneous somatic mutation
1 RB mutated in retinoblastoma
Sporadic two hit point
Both RB must undergo somatic mutation in the same retinoblast
Genetic trait associated with germ line mutation in RB
Autosomal
Loss of function mutations in the RB gene
Recessive
Child is normal if carrying
Inherited mutant RB in all somatic cell
Inhibitor of mitogenic signaling pathways
APC NF1 NF2 PTCH PTEN SMAD2 SMAD4
Inhibitor of cell cycle progression
RB
CDKN2A
Inhibitor of RAS/MAPK signaling
NF1
Inhibitor of WNT signaling
APC
Inhibitor of PI3K /AKT signaling
PTEN
Inhibitor of G1/S
RB
P16
P14
Indirect activator of p53
CDKN2A
Cell cycle arrest and apoptosis in response to DNA damage
TP53
Activator of AMPK family of kinases
STK11
Cell adhesion’ inhibition of cell motility
Altering cell metabolism
STK11
Genomic stability
BRCA1 and BRCA2
Governor of proliferation
RB
RB loss of function
Mutation involving both RB alleles
Mutation that end CDK inhibitors
Active hypo phosphorylated
RB gain of function
Up regulate CDK/cyclin D
Inactive hyper phosphorylated state
Complexes lead to hyper phosphorylation and inhibition of RB
CDK 4/ cyclin D
CDK 6/ cyclin D
CDK 2/ cyclin E
Up regulate activity of CDK/cyclin
Growth factor signaling pathway
Why do patients with germ line RB mutations preferentially develop only a few type of cancer?
Other RB family exist that may partially complements RB function
Why mutations of RB are not more widespread in human tumors?
Other genes can mimic the effect of RB loss
Guardian of the genome
TP53
Most frequent mutated gene in human cancers
TP53
TP53 regulates
Cell cycle progression
DNA repair
Cellular senescence
Apoptosis
Loss of function of TP53 located on
Chromosome 17p13.1
3 leading cause of cancer death, Tp53
Lung
Colon
Breast
Somatic cells not inherited in germ lines
Inheritance of TP53
Inheritance of TP53
Only one additional hit
Li fraumeni syndrome
Develop cancer at young age
25 folds
Malignant tumor by 50 yo
Stimulate the degradation of p53
MDM2 and family
Viral oncoprotein that binds to p53 that promote degradation
E6 protein
Kapag na disrupt o hindi nag bind si MDM2 at p53
Mac aacumulate si p53 which is good
Paano a di disrupt ang binding ng MDM2 at p53
DNA damage ( ATM and ATR) Oncogenic stress ( ARF binds to MDM2) dispalce p53
Once activated p53 induced
Cell cycle arrest
Senescence
Programmed cell death
Successful repair
P21 (CDk inhibitor)
GADD 45
Transient p53 induced cell cycle arrest
CDKN1A to CDK inhibitor p21
GADD45
Decrease CDK =
Loss of function
Active hypo phosphorylation
Blocked G1 phase to s phase
Increase CDK4 =
Gain of function
Inactive hyper phosphorylation
Proceed G1 phase to S phase
RB inhibition
Encodes a factor that negatively regulates the WNT
APC
Colon carcinomas
APC
Contact mediated growth inhibition of epithelial cells
Signaling protein that functions in the WNT pathway
E Cadherin
Suppressive proteins, p16/ INK4a a cyclin dependent inhibitor that augment RB function and ARF which stabilize p53
CDKN2A
Potent inhibitor of cellular proliferation
TGF beta pathway
Encodes a lipid phosphatase that is an important negative regulator of PI3K/AKT
PTEN
Encodes neurofibronmin 1
A gtpase that acts as a negative regulator of RAS
NF1
Encodes neurofibronmin 2 (merin)
Cytoskeletal protein in contact inhibition
NF2
Encodes a transcription factor that is required for normal development of genitourinary tissues
WT1
Encodes membrane receptor that is a negative regulator of the Hedeghog signaling pathway
PTCH1
Encodes a component of a ubiquitin ligase that is responsible for degradation of hypoxia induced factors
VHL
Recognizes genotoxic stress and shutting down proliferation
RB
P53
