CBIO 2 Oncogenes & tumour suppressor genes

Oncogenes & tumour suppressor genes - tumour dvlp: activation of oncogenes, inactivation of tumour suppressor genes Key concepts - proto-oncogene = normal gene which, when changed by a mutation becomes an oncogene - oncogene = encodes for a p whose activation, overexpression or mutation promotes oncogenesis - oncogenesis = carcinogenesis = process through which healthy cells become cancer cells - oncovirus = virus that can cause cancer - retrovirus = copy & integrate their genome into the chr of a host cell (HIV, virus of AIDS...) Tumour suppressor genes - normal gene which can slow down cell growth/ division, repair DNA mistakes & promote apoptosis => if absence, repression, inactivation, loss-of-function mutation: cancer => like a brake pedal of a car - 1 functional copy of the gene produces enough p to prevent oncogenesis => both copies need to be mutated to inactivate gene => mutations in tumour suppressor genes are recessive - inherited abnormalities in familial cancer syndromes (APC gene mutation => colon cancer) => BUT most are acquired (TP53 mutation => codes for p53 => more than half human cancers) - gatekeeper tumour suppressor gene: negatively regulate cell growth (ex: Rb) => inhibit proliferation or angiogenesis, induce apoptosis or cell adhesion - caretaker tumour suppressor gene: maintain chr integrity (ex: p53) => repair DNA damage Retinoblastoma - rare, affects children: cancerous tumour of the retina (specifically in light-sensitive lining) - during dvlp: retinal cells grow rapidly but stop => when continue: retinoblastoma - 40%: mutation in RB1 gene (inherited/ acquired in early dvlp) => bilateral (affects both eyes) 60%: no mutation (not understood) => unilateral (affects 1 eye) - if detected early: 95% treatment success (can be fatal) - G1 checkpoint before replication (S) => transcription factor E2F allow cells to enter S-phase => start the building of proteins/ enzymes for replication => E2F inactivated by Rb protein (1 is sufficient) => replication IF Rb inactivated by phosphorylation => if mutation => continuous replication => cancer - “two-hit” Knudson hypothesis of tumour suppressor genes: => both copies need to be mutated to inactivate gene => inherited: inherited mutation = 1st hit ; mutation of normal copy = 2nd hit => spontaneous: 2 mutations (lower chances and require more time: older & only 1 tumour) - at cellular level: recessive BUT if inherited mutation => predisposition passed as a dominant trait (only need 1 mutation in the normal allele) - RB1 mutated in most cancers: P53 tumour suppressor - guardian of the genome - transcription factor p53: encoded by TP53 on chr 17 => prevents mutations + stabilises genome - Loss of Heterozygosity (LOH) involved in cancer dvlp: loss of a wild type allele, loss/ inactivation of a gene, duplication allele... (can’t bind E2F) - mutation in a repair p can have indirect effects if causes increased inactivation of other tumour suppressor genes/ activation of oncogenes - expressed in nearly all cells + mutated in 50% cancers (mainly ovary, oesophagus, colorectal cancers...) 1) arrest at G1/S checkpoint if damage (upregulate cdk inhibitor p21) => reversible or irreversible (senescence) 2) regulate NER (promote expression of genes of DNA repair) regulate BER (directly interacts w/ p and DNA pol) 3) block angiogenesis (represses pro-angiogenic genes) BUT enhance angiogenesis in some cases 4) apoptosis & mitochondrial permeabilisation if damage (activate Bax p => binding caspase to cyt c) - often spontaneous BUT inheritance of mutation in Li-Faumeni syndrome (predisposition to cancer) - normally, Mdm2 E3-ubiquitin keeps levels of p53 low => binds to transactivation domain => no transcription factor activity => promotes movement of p53 out of the nucleus => degraded by proteasome in the cytosol via ubiquitin pathway - in stressed cells: p53 is stabilised (= not degraded) => phosphorylation (by p kinases: ATM...) of p53 prevents binding => ARF protein binds to Mdm2 instead - if loss p53 => no cell cycle arrest - if elevated p53 (gain of function mutation) => cell cycle arrest + apoptosis of tumour suppressors Oncogenes - gain of function mutations => dominant => only need 1 mutated allele - viral oncogenes: RSV virus in chickens (carry a tumorigenic factor: gene v-src) => cancerous cells had changes in cellular phenotype (altered membrane, adherence, proliferation) How are oncogenes activated? - proto-oncogenes promote cell growth BUT when mutate => permanently turned on => oncogene (like the accelerator of a car stuck down) - most cancer-causing mutations are acquired (rarely inherited) => chr rearrangement: deletions, duplications, inversions, translocations => gene duplication/ amplification: additional gene copies => pt mutation Mutation examples - proto-oncogene activation can lead to: - increased protein conc (1) - increased enzyme/ protein activity (2) - regulation loss - Ras (GTPase proto oncogene): binds GDP in its inactive state => replaced by GTP (w/ GTP exchange factor (GEFs)) when activated (growth factors signals) => activate transcription factors => control proliferation, survival + differentiation => Ras deactivated w/ its GTPase activity + GTPase activity accelerating protein (GAPs) - if Ras mutated => GTP remains => uncontrolled cell division (without growth factors) - Ras subfamily contains HRas, KRas, NRas (mutations are common) => code for 4 homologous Ras proteins => identical effector binding domain BUT ≠ posttranslational modif => ≠ signalling pathways - Myc family of oncogenes: regulate many p coding and non coding genes Chromosomal rearrangements - translocations: segment of a chr moved to a new location (often leukaemia & lymphomas) => joining of a proto-oncogene with regulatory regions => increased expression => merging of 2 genes that code a new oncogenic p - Burkitt’s lymphoma: region of chr 8 exchanged w/ a region of chr 14 => oncogene MYC mapped at the chr 8 breakpoint & IgH gene at chr 14 breakpoint => MYC promoter replaced by that of IgH (which promote continuous expression) => over expression of fusion p TUMOUR SUPPRESSOR GENES (RB-1 & p53): Double agents - POTSF: proto-oncogenes with tumour-suppressor functions (depending on cancer type) => 1 mutation can release oncogenic & eliminate tumour-suppressor function: “one-hit” cancer - ex: NOTCH receptors, TP53 (p53), FAS