Oncogenes + Tumour Suppressor Genes Flashcards
Describe homeostasis
Interplay between +tive and -tive growth regulators
What can a loss of growth control result from
Activation of +tive regulators
Inactivation of -tive regulators
What can cause an increased or prolonged growth signal
RAS mutation where it is no longer recognised by GAP proteins
Deletion/mutation of GAP genes
How is Ras activated
Displacement reaction from GTP -> GDP
What is the role of GTPase in RAS
Intrinsic activity that brings RAS to ground state
Accelerated by GAP proteins
What can a loss of GAP proteins cuase
Constitutively active RAS pathway
What is evidence of tumour suppressor genes
Cell hybrid studies
Familial cancers
Non-random chromosome losses in tumours
What is the concept of cell hybrid studies
Normal cells can suppress the transformed and tumourigenic phenotype
Cells that revert to a transformed phenotype show loss of specific chromosomes
What does the fusion of different tumour cell limes imply
Can produce normal cell hybrids
= different tumour cells have different recessive mutations
Describe the Knudson 2-hit hypothesis
Inheritance of a single mutated allele from one parent
Second ,auction in the normal allele during development
= tumour
Describe of the characteristics of the RB gene and product
Accosted with DNA but not directly bound
Expressed abundantly in most normal tissues
What is the function of the RB protein in transcriptional regulation
Binds and regulation TFs and cell cycle control proteins
What is the function of the RB protein in cell cycle control
G0/G1: RB hypo-phosphorylated when bound to E2F -> E2F= inactive
Progression: RB phosphorylation = dissociation of the E2F/RB complex -> releases E2Fs TF activity
What is the role of TF E2F
Drives expression of genes required into S-phase
E.g enzymes required for synthesis of DNA and precursors
What is the relationship between RB and patients with non-occular tumours
Shows an increased risk
Particularly in osteosarcomas and soft-tissue sarcomas
Structural abnormalities of RB gene found
What is the relationship between RB protein expression and prognosis in breast and bladder cancers
Low levels of RB = invasive lesions and poor prognosis
Describe the karyotype in sporadic tumours
Unstable
Gains, losses and rearrangements = not random
17p deletions are common
What is the critical region of chromosomal deletions in colorectal cancer
17p12-17p13.3
What gene is also mapped to the 17p12-12p13.3 regions
TP53
Gene for p53
Describe the TP53 mutation
Missense mutation in 1 allele
Coupled with loss of second allele
Describe TP53 gene
Deleted in a wide range of common cancers
Compromises of 11 exons
Exons 2-10 code for p53 protein
Describe the p53 nuclear phosphoprotein structure
N-terminal: acidic transcription transactivation domain
Central region: DNA biding domain
C-terminal: basic and binds to other p53 to form oligomers
Where in the p53 protein do the mutations occur
Within central binding domain
+tively charged arginine residues
Critical for structure and binding to DNA
Where is the MDM2 binding domain on p53
N-terminal domain
Heavily phosphorylated
