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Describe the mechanism by which mutations in tumour suppressor genes can lead to the development of cancer?? Concentrate primarily on the RB and p53 genes??

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Presentation on theme: "Describe the mechanism by which mutations in tumour suppressor genes can lead to the development of cancer?? Concentrate primarily on the RB and p53 genes??"— Presentation transcript:

1 Describe the mechanism by which mutations in tumour suppressor genes can lead to the development of cancer?? Concentrate primarily on the RB and p53 genes?? but give examples of other genes if you come across significant differences in the way in which they act?? MRCPath Self Help Course 12 th January 2010 Mai M Abd El-Aziz

2 Tumour Suppressor genes (TS) One of three major classes of genes  tumorigenesis One of three major classes of genes  tumorigenesis Inactivation of TS  development of cancer Inactivation of TS  development of cancer Inactivation arise from Inactivation arise from 1. Missense mutations 2. Nonesense mutations 3. Deletions 4. Insertions 5. Epigenetic silencing Mutations in M & P alleles are needed  selective advantage to the cell Mutations in M & P alleles are needed  selective advantage to the cell Exceptions: inactivation of one allele can also exert the same action on the cell through haploinsufficiency Exceptions: inactivation of one allele can also exert the same action on the cell through haploinsufficiency

3 How TS genes operate? Mutations in TS genes drive the neoplastic process by increasing tumour cell number through Mutations in TS genes drive the neoplastic process by increasing tumour cell number through 1. Stimulation of cell birth 2. Inhibition of cell death/cell cycle arrest Mutations in TS can be either Mutations in TS can be either 1. Germline  hereditary predisposition to cancer 2. Somatic  sporadic tumours The first mutation  clonal expansion & initiate the neoplastic process The first mutation  clonal expansion & initiate the neoplastic process Subsequent mutations  additional rounds of clonal expansion  tumour progression Subsequent mutations  additional rounds of clonal expansion  tumour progression

4 TS Genes and Pathways PathwaysGenesDisease RBRB1CDKN2A Hereditary retinoblastoma Familial malignant melanoma P53TP53WT1 Li Fraumeni syndrome Familial Wilms tumour APCAPCFAP HIF1VHL Von Hipple-Lindau syndrome PI3K TSC1, TSC2 Tuberous sclerosis RTKNF1Neurofibroma SMADMEN1 Multiple endocrine neoplasia type I

5 pRb and p53 pathways Loss of function of both p53 and the pRB pathways play a significant role in the development of most human cancers pRb regulates apoptosis during development, and its loss results in deregulated cell proliferation and apoptosis p53, however guards against genomic instability and oncogene expression by inducing both arrest of the cell cycle and apoptosis hence its loss will desensitise cells to checkpoint signals, including apoptosis All DNA tumor viruses that cause tumours in experimental animals or humans encode proteins that inactivate both pRb and p53 All DNA tumor viruses that cause tumours in experimental animals or humans encode proteins that inactivate both pRb and p53

6 The retinoblastoma paradigm The retinoblastoma paradigm Knudson in 1971 proposed that all retinoblastomas involved two hit mechanisms Knudson in 1971 proposed that all retinoblastomas involved two hit mechanisms In the familial cases one hit was inherited In the familial cases one hit was inherited In the sporadic cases both hits occurred somatically to inactivate the RB gene In the sporadic cases both hits occurred somatically to inactivate the RB gene Complications of the RP paradigm Complications of the RP paradigm BRCA1 is inactivated in only 10-15%, when inactivation happens is not by chromosomal mechanisms but by DNA methylation BRCA1 is inactivated in only 10-15%, when inactivation happens is not by chromosomal mechanisms but by DNA methylation Some genes lose function of one allele in tumours, but the retained allele appears fully functional Some genes lose function of one allele in tumours, but the retained allele appears fully functional Cases with three hits, eg, APC certain germline mutations are weak and hence two somatic mutations in addition to the inherited one are needed Cases with three hits, eg, APC certain germline mutations are weak and hence two somatic mutations in addition to the inherited one are needed

7 The RB pathway pRb functions as a gatekeeper pRb functions as a gatekeeper -vely regulates progression through the G1 phase of the cell cycle -vely regulates progression through the G1 phase of the cell cycle During the G1 phase pRb is hypo(P) (Active)  binds E2F  repression of E2F-mediated transcription In late G1 and through the M phase pRb is (P) i.e. inactivated by CDK  E2F is released  promote the expression of genes required for cell division. P16 inhibits CDK4/6 kinase P16 inhibits CDK4/6 kinase Loss of P16 function  loss of pRb function  inappropriate cell cycling

8 The RB pathway cont. pRb repression of E2F is believed to be mediated by recruiting chromatin remodelling complexes to the E2F promoter during the resting phase (G0/G1) SWI/SNF complex, histone deacteylases, polycomb proteins and methylases are examples of chromatin remodelling complexes that interacts with pRb pRb is a member of the pocket proteins which includes p107& p130 pRb interacts with E2F1-4 whereas p107 interacts with E2F4, p130 interacts with E2F5

9 Potential functions of RB Besides cell cycle regulation Besides cell cycle regulation DNA damage responses DNA damage responses DNA repair DNA repair DNA replication DNA replication Protection against apoptosis Protection against apoptosis Differentiation Differentiation Rb -/- mice die between days gest. P170 or p130-null mice develop normally Rb+/-  predisposition to pitut & thyroid tumours Rb+/-&p53 del  retinal dysplasia

10 TP53 The TP53 gene encodes a 53 kDa phosphoprotein which belongs to small family of related proteins (p63 & p73) 95% of the mutations were found to occur in the central DNA binding core of p53 Nearly 28% of mutations affect only six residues (shown) Over 90% of the mutations lead to single amino acid substitutions

11 p53 pathway This is by covalent modification involving phosphorylation of the transactivation domain, and acetylation and phosphorylation of the basic allosteric control region Normally, levels of p53 are low due to the short half-life of the protein Stress signals (DNA-damaging agents, such as ultraviolet or γ irradiation and chemotherapeutic drugs) can induce the stabilisation and activation of p53

12 p53 activation (UV) (IR) Phosphorylate p53 ATM kinase ATR kinase A) Stress Activation of p53 Can be activated by both external and internal aberrations B) Deregulation of cellular oncogenes Expression of P14 (ARF) Deactivation of MDM2 Blocking the degradation of P53 Activation of P53

13 How P53 prevents tumour formation ?? First, it arrests the G1/S transition to allow DNA repair to happen Second, it can transcriptionally activate DNA repair proteins Last, if DNA repair fails then it will induce apoptosis

14 Arresting the G1/S transition phase By activating the transcription of the gene encoding P21  Inhibition of CDK4/cyclinD1 & CDK2/cyclin E complexes  Blocking of the G1/S transition phase

15 P53 apoptosis pathway

16 APC pathway & FAP Absence of WNT signal  phosphorylation of  -catenin at multiple residues This is dependent on a multiprotein complex made of APC, Axin and GSK3  (P)  -catenin will be degraded by ubiquitin and proteosome pathway WNT sig.  stabiliz. of  -catenin & its accumul. in the cytoplasm  move to the nucleus where it leads to transcription of target genes Mut. Of APC    -catenin   transcrip. Of genes & TCF APC downregulate the WNT pathway by acting as a shuttle for  -catenin

17 HIF1 Pathway & VHL VHL in presence of oxygen VHL in presence of oxygen  degrade HIF1 In absence of O 2 or if VHL is mutated  HIF1 will be stabilized  Expression of VEGF  stim. of angiogenesis

18 Implication of oncogenes and TS genes in the process of angiogenesis

19 References Retinoblastoma: revisiting the model prototype of inherited cancer. Lohmann DR and Gallie BL (2004) Am J Med Genet, 129C The retinoblastoma tumour suppressor in development and cancer. Classon M and Harlow E (2002) Nat Rev Cancer, 2, The p53 tumour suppressor gene. Steele RJ at al (1998) Br J Surg, 85, The p53 tumour suppressor gene. Live or let die: the cell's response to p53. Vousden KH and Liu X (2002) Nat Rev Cancer,2, Live or let die: the cell's response to p53. The role of p53 and pRB in apoptosis and cancer. Hickman ES, Moroni MC, Helin K. Curr Opin Genet Dev Feb;12(1):60-6. Review The role of p53 and pRB in apoptosis and cancer. Apoptosis - the p53 network. Haupt S, Berger M, Goldberg Z, Haupt Y. J Cell Sci Oct 15;116(Pt 20): Haupt SBerger MGoldberg ZHaupt Y Tumour suppressor genes: Pathways and isolate strategies by Wafik S. El-Deiry Vogelstein B and Kinzler KW (2004) Nat Med, 10,


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