Oncogenes: Tumour Suppressor Genes 2

L5: TUMOUR SUPPRESSOR GENES [03/10/2022]



I. TUMOUR SUPPRESSOR GENES (TSGs): can be considered the ‘brakes’ of the cell for
keeping a check on unwanted growth.

Loss of Function:

 Functionally RECESSIVE – both copies of gene must undergo a deactivating mutation in order
to have an effect.

Familial Cancers:

, II. HOW CAN TUMOUR SUPPRESSOR GENES BE LOST?
 Mutation
 Deletion
 Loss of heterozygosity (allelic deletion)
 Methylation
 Up-regulation of oncogenic miRNAs (insertion of retrotransposons)
 Haploinsufficiency

III. WHAT SORTS OF GENES CAN BE TUMOUR SUPPRESSOR GENES?
 Signalling – Smad4, DCC, APC
 Transcription – WT-1, p53
 Gene Expression – VHL
 Cell Cycle Control – pRb, p53
 Cell Adhesion – E-cadherin
 Cytoskeletal Architecture – NF-2
 DNA Damage and Repair – p53, ATM, BRCA1/2
 miRNAs – let-7 (targets ras and myc)

IV. NF1
 GTPase-activating protein (GAP) for Ras provokes Ras to activate intrinsic GAP activity
 NF1 expressed throughout the body, but especially n adult PNS and CNS
 Upon growth factor stimulation, NF1 degraded, RAS signalling proceeds. After 60-90 mins
NF1 levels back to normal, shuts down Ras signalling
 Loss of NF1 mimics activated Ras



V. PTEN
 Mutations in NF1 and PTEN affect linked pathways leading to proliferation and survival.



VI. APC
 Familial adenomatous polyposis (FAP)
- inherited susceptibility to develop adenomatous polyps in colon (1 in 8000)
- polyps are non-malignant, but are prone to develop m=into carcinomas at a low but
predictable frequency



 in the absence of Wnt
(but presence of APC)
β-catenin levels are
low, TLE represses
TCF mediated gene
expression