NEOPLASIA 2

Notes:	Hide Notes

Slide 1: NEOPLASIA 2 Click to edit Master subtitle style F e A . B a rt o lo m e , MD, F P A S MA P De pa rt m e n t o f P a th o lo g y O u r L a dy o f F a tim a U n iv e rs ity 10/20/09 Slide 2: M O L E C U L A R B A S I S Principles Non-lethal genetic damage lies at the heart of carcinogenesis. • 1. May be acquired (environmental agents or viruses) OR inherited in the germ line Environmental – exogenous agents or endogenous products of cell metabolism • 10/20/09 Slide 3: M O L E C U L A R B A S I S Principles A tumor is formed by the clonal expansion of a single precursor cell that has incurred the genetic damage s • 2. As tumors develop they undergo further somatic mutation d composed of a set of slightly different cells (tumor heterogeneity) y control more abnormal and facilitate metastasis 10/20/09 Slide 4: 10/20/09 Slide 5: M O L E C U L A R B A S I S Principles 3. Four classes of regulatory genes are the principal targets of genetic damage. a) Protooncogenes (p-oncs) • Genes that code for proteins involved in the control of cell growth (e.g. Growth factors, growth factor receptors, signal transducers) • Mutant alleles dominant u transform cells despite presence of normal counterpart p phenotype affected even if one allele is present 10/20/09 Slide 6: M O L E C U L A R B A S I S Principles 3. Four classes of regulatory genes are the principal targets of genetic damage. b) Tumor suppressor genes • Genes that produce products that inhibits cell growth o control G1 to S phase of cell cycle & nuclear transcription • Both normal alleles must be damaged for transformation to occur d recessive oncogenes r malignant phenotype only develops if both alleles fail to suppress growth 10/20/09 Slide 7: M O L E C U L A R B A S I S Principles 3. Four classes of regulatory genes are the principal targets of genetic damage. c) Apoptosis genes • Regulate programmed cell death • Example: BAX apoptosis gene ü Activated by TP53 if DNA damage is excessive ü BAX protein inactivates the BCL2 anti-apoptosis gene ü Mutation of TP53 n inactivate BAX t no apoptosis 10/20/09 Slide 8: M O L E C U L A R B A S I S Principles Four classes of regulatory genes are the principal targets of genetic damage. d) 3. Genes involved in DNA repair • Loss of activity L somatic mutations in oncogenes or tumor suppressor genes • Both alleles must be inactivated 10/20/09 Slide 9: M O L E C U L A R B A S I S Principles Carcinogenesis is a multistep process at both the phenotypic and the genetic levels • 4. • Phenotypic attributes of malignant neoplasms are acquired in a stepwise fashion called tumor progression Progression results from accumulation of genetic lesions (multiple mutations) 10/20/09 Slide 10: 10/20/09 Slide 11: Tumor progression and genetic heterogeneity. As tumors develop they undergo further somatic mutation, which causes abnormalities in other oncogenes. Mutations may also lead to cell death. A mutation that puts a cell at a survival disadvantage will 10/20/09 cause that clone to be eliminated. A tumor will ultimately consist of Slide 12: M O L E C U L A R B A S I S Fundamental Changes in Cell Physiology That Determine Malignant Phenotype 1. 2. 3. 4. 5. 6. 7. Self-sufficiency in growth signals Insensitivity to growth-inhibiting signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize Defects in DNA repair 10/20/09 Slide 13: M O L E C U L A R B A S I S Self-sufficiency in growth signals A. Oncogenes • Genes that promote autonomous growth in cancer cells • Unmutated counterparts called proto-oncogenes • Created by mutations in protooncogenes • Products similar to normal counterparts but lacks important internal regulatory elements r endow the cell with self-sufficiency in growth 10/20/09 Slide 14: M O L E C U L A R B A S I S Self-sufficiency in growth signals Normal Cell Proliferation Binding of growth factor to receptor Activation of signaltransducing proteins on inner leaflet of plasma membrane Entry and progression into cell cycle Transmission of signal across cytosol s nucleus Initiate DNA transcription Induction and activation of nuclear regulatory factors 10/20/09 Slide 15: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 1. Growth factors • • Most soluble growth factors made by one cell type and act on a neighboring cell to stimulate proliferation b paracrine action Most cancer cells able to synthesize the same growth factors to which they are responsive in an autocrine loop 10/20/09 Slide 16: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 2. Growth factor receptors • Normal transmembrane receptors: cytoplasmic tyrosine kinase transiently activated c dimerization and tyrosine phosphorylation Oncogenic version: with constitutive dimerization and activation without binding to the growth factor b continuous mitogenic signal to cell even in the absence of growth factors in the environment 10/20/09 • Slide 17: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 2. • Growth factor receptors Mechanisms of constitutive activation of GFRs: a) Mutations and gene rearrangements ü RET protein normally expressed in neuroendocrine cells § § Point mutation in extracellular domain u adrenal, and parathyroid tumors) Point mutations in cytoplasmic domain u MEN 2B (thyroid and adrenal tumors) 10/20/09 Slide 18: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 2. Growth factor receptors • Mechanisms of constitutive activation of GFRs: a) Mutations and gene rearrangements ü FLT3 gene i code for FMS-like tyrosine kinase 3 receptor § Point mutation myeloid leukemias 10/20/09 Slide 19: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 2. Growth factor receptors • Mechanisms of constitutive activation of GFRs: b) Overexpression of normal forms of GFRs ü More common ü ERBB1 (EGF receptor gene) r 80% of squamous cell Ca of lungs ü ERBB2 (HER-2/NEU) l breast Ca, adenocarcinoma of ovary 10/20/09 Slide 20: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 3. Signal-Transducing Proteins • • Located on inner leaflet of the plasma membrane n receive signals from outside the cell e transmit to cell’s nucleus Most well studied is RAS family of GTPbinding proteins (G proteins) 10/20/09 Slide 21: M O L E C U L A R B A S I S Self-sufficiency in growth signals RAS Oncogone (HRAS, KRAS, NRAS) • Point mutation of proto-oncogene the single most common abnormality in human tumors Located at cytoplasmic aspect of plasma membrane as well as membranes of ER and Golgi RAS proteins bind guanosine nucleotides 10/20/09 • • Slide 22: M O L E C U L A R B A S I S Self-sufficiency in growth signals RAS Oncogone Stimulation of cells by growth factors Hydrolysis of GTP Inactive RAS GDP Exchange of GDP for GTP Activated RAS Stimulate mitogenactivated protein (MAP) 10/20/09 kinase cascade Flood nucleus with signals for cell proliferation Slide 23: M O L E C U L A R B A S I S Self-sufficiency in growth signals RAS Oncogone 10/20/09 Slide 24: M O L E C U L A R B A S I S Self-sufficiency in growth signals RAS Oncogone Activation of oncogenic RAS leads to upregulation of INK4A t CDK4-mediated hyperphosphorylation (P) of RB S provokes cellular senescence. RAS signalling might also feed into the ARF–p53 pathway to promote apoptosis as well as reinforce cellular senescence. 10/20/09 Slide 25: M O L E C U L A R B A S I S Self-sufficiency in growth signals RAS Oncogone • Mutated RAS trapped in its activated GTP-bound form due to inactivation of GTP hydrolysis d cell forced into a continuous proliferative state Mutations of KRAS r carcinomas of colon and pancreas Mutations of HRAS r bladder tumors Mutations of NRAS r hematopoietic tumors 10/20/09 • • • Slide 26: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 4. Transcription factors Transducing signals Stimulation of nuclear transcription factors Bind DNA or dimerize for DNA binding DNA transcription 10/20/09 Slide 27: M O L E C U L A R B A S I S Self-sufficiency in growth signals Role of Oncoproteins 4. Transcription factors • Ultimate consequence of signalling through oncogenes is inappropriate and continuous stimulation of nuclear transcription factors Growth autonomy occurs as a consequence of mutations affecting genes that regulate transcription (e.g. MYC) 10/20/09 • Slide 28: M O L E C U L A R B A S I S Self-sufficiency in growth signals MYC Oncogone • Proto-oncogene expressed in all eukaryotic cells p immediate response genes o rapidly induced when quiescent cells receive signal to divide Target genes of oncogene: include ornithine decarboxylase and cyclin D2 o associated with cell proliferation • 10/20/09 Slide 29: M O L E C U L A R B A S I S Self-sufficiency in growth signals MYC Oncogone • Range of activities modulated by MYC: 1. 2. 3. 4. 5. 6. Histone acetylation Reduced cell adhesion Increased cell motility Increased telomerase activity Increased protein synthesis Decreased proteinase activity 10/20/09 Slide 30: M O L E C U L A R B A S I S Self-sufficiency in growth signals MYC Oncogone • Range of activities modulated by MYC: 7. Selection of origins of replication overexpression i more origins of replication needed for normal cell replication 8. Bypass checkpoints involved in replication 9. Re-programming of cells into pluripotent stem cells 10. Enhance self-renewal, block differentiation or both 10/20/09 Slide 31: M O L E C U L A R B A S I S Self-sufficiency in growth signals MYC Oncogone • Persistent expression commonly found in tumors Translocation r Burkitt’s lymphoma Amplification r carcinoma of breast, colon, lungs, and other carcinomas • • 10/20/09 Slide 32: c-MYC sensitizes cells to a wide range of proapoptotic stimuli. During apoptosis, c-MYC induces release of cytochrome c from the mitochondria into 10/20/09 the cytosol, possibly through activation of the pro- Slide 33: 10/20/09 Slide 34: 10/20/09 Slide 35: 10/20/09 Slide 36: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs Normal Cell Cycle: • Orderly progression of cells through cell cycle orchestrated by CDKs bound to cyclins • CDK-cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle • Cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs 10/20/09 Slide 37: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs Normal Cell Cycle: • Inhibitors of CDKs (CDKIs) 1. CIP/WAP family D broadly § p21, p27, p57 2. INK4 family 7 with selective action on cyclin D/CDK4 and cyclin D/CDK6 § p15, p16, p18, p19 10/20/09 Slide 38: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs Normal Cell Cycle: • Cell cycle checkpoints 1. G1/S checkpoint o Checks for DNA damage t prevent replication of cells with defects in DNA Monitors completion of DNA & checks whether cell can safely initiate mitosis l important in cells exposed to ionizing radiation 10/20/09 2. G2/M checkpoint o Slide 39: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs Normal Cell Cycle: • Cell cycle checkpoints ü Require: 1. Sensors of DNA damage Ø Proteins of RAD family & ataxia telangiectasia mutated (ATM) 2. Signal transducers Ø CHK kinase family 10/20/09 Slide 40: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs Normal Cell Cycle: • Cell cycle checkpoints ü Require: 3. Effector molecules Ø G1/S t p53 and p21 Ø G2/M t p53-dependent and p53-independent mechanisms 10/20/09 Slide 41: 10/20/09 Slide 42: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs • Mutations that dysregulate activity of cyclins and CDKs favor cell proliferation Mutations affecting expression of cyclin D or CDK4 common in neoplastic transformation ü Cyclin D overexpression l Ca of breast, esophagus, liver, lymphomas ü Amplification of CDK4 e melanomas, sarcomas, glioblastomas 10/20/09 • Slide 43: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs • CDKIs frequently mutated or otherwise silenced in many human malignancies ü Somatically acquired deletion or inactivation of p16 pancreatic Ca, glioblastomas, esophageal cancers, ALL, bladder cancers ü Germline mutations of p16 c melanoma 10/20/09 Slide 44: M O L E C U L A R B A S I S Self-sufficiency in growth signals B. Dysregulated activity of cyclins & CDKs • Defects in cell cycle checkpoint components are a major cause of genetic instability in cancer cells. 10/20/09 Slide 45: M O L E C U L A R B A S I S Insensitivity to growth inhibition & escape from senescence Tumor Suppressor Genes • Apply breaks to cell proliferation & prevent uncontrolled growth Recognize genotoxic stress e shut down cell proliferation Expression of oncogene in a normal cell s lead to quiescence or permanent cell cycle arrest (oncogene-induced senescence) 10/20/09 • • Slide 46: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • RB protein a ubiquitously expressed nuclear phosphoprotein Exists in an active hypophosphorylated state in quiescent cells and an inactive hyperphosphorylated state in the G1/S cell cycle transition • 10/20/09 Slide 47: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • Important in its enforcement of G1 µ cells can exit the cell cycle either temporarily (quiescence), or permanently (senescence) ( induce senescence RB also controls stability of the cell cycle inhibitor p27 • 10/20/09 Slide 48: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • Blocks E2F-mediated transcription by: 1. E2F sequestration E prevent E2F from interacting with other transcriptional activators 2. Recruitment of chromatinremodelling proteins (histone deacetylases & histone methyltransferases) r bind to E2Fresponsive genes (e.g. Cyclin E) 10/20/09 Slide 49: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • Hypophosphorylated (active) RB · binds to and inhibits E2F ) no cyclin E transcription n progression to S phase inhibited Hyperphosphorylated RB 2 inactive RB c release of E2F a (+) transcription of cyclin E ) (+) DNA replication and progression through cell cycle 10/20/09 • Slide 50: 10/20/09 Slide 51: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • Absent RB due to gene mutation · no regulation of E2F transcription factors r (+) DNA replication and continuous progression through cell cyle 10/20/09 Slide 52: M O L E C U L A R B A S I S Tumor Suppressor Genes: RB (retinoblastoma) • Mutations in other genes that control RB phosphorylation can mimic the effect of RB loss ü Mutational activation of cyclin D or CDK4 i facilitate RB phosphorylation ü Mutational inactivation of CDKIs unregulated activation of cyclins and CDKs 10/20/09 Slide 53: M O L E C U L A R B A S I S • Loss of normal cell cycle control is central to malignant transformation. At least one of the following regulators of the cell cycle is dysregulated in majority of human cancers: 1. p16/INK4a 3. CDK4 2. cyclin D 4. RB • 10/20/09 Slide 54: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • • • • TP53 gene located at chr. 17p13.1 Most common target for genetic alterations in human tumors Sense cellular stress, such as DNA damage, shortened telomeres, and hypoxia Functions as a critical gatekeeper against the formation of cancer e “molecular policeman” or “guardian of the genome” 10/20/09 Slide 55: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • p63 and p73 s p53 collaborators ü p53 ubiquitously expressed while p63 and p73 with more tissue specificity ü p63 essential for differentiation of stratified squamous epithelia ü p73 with strong pro-apoptotic effects after DNA damage from chemotherapeutic agents 10/20/09 Slide 56: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • Prevents malignant transformation by: 1. Activation of temporary cell cycle arrest (quiescence) 2. Induction of permanent cell cycle arrest (senescence) 3. Triggering of programmed cell death (apoptosis) 10/20/09 Slide 57: M O L E C U L A R B A S I S DNA-damaging agents/hypoxia Activation of normal p53 Up-regulation of GADD45 genes Up-regulation of CDKI p21 Cell cycle arrest in G1 Successful repair Induction of DNA repair Unsuccessful repair Cell cycle progression Activate mir34 Stimulate BAX Inhibit growthpromoting genes (MYC, CDK4) Quiescence/ senescence Inhibit antiapoptosis genes (BCL-2) Apoptosi s 10/20/09 Slide 58: M O L E C U L A R B A S I S Summary of the mechanism of action of the tumor suppressor protein, p53. 10/20/09 Slide 59: M O L E C U L A R B A S I S DNA-damaging agents/hypoxia Cells with mutations or loss of p53 Cell cycle progression No activation of p53dependent genes No DNA repair No senescence DNA damage MALIGNANT TUMOR Expansion & additional mutations Mutant cells 10/20/09 Slide 60: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • Homozygous loss of p53 occurs in virtually every type of cancer ü In most cases, inactivating mutations affect both p53 alleles and are acquired in somatic cells. Approximately 80% of p53 point mutations present in human cancers are located in the DNA-binding domain of the protein 10/20/09 • Slide 61: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • In the majority of tumors without p53 mutations, the function of the p53 pathway is blocked by mutation in another gene that regulates p53 function ü MDM2 and MDMX h stimulate degradation of p53 m overexpressed in malignancies v Amplification of MDM2 v human sarcomas 10/20/09 Slide 62: M O L E C U L A R B A S I S Tumor Suppressor Genes: p53 • mir34 microRNAs important to p53 response r targets include proproliferative genes such as cyclins and anti-apoptotic genes (BCL-2) ü Inhibition or blockage of mir34 i impaired p53 response ü Ectopic expression of mir34 without p53 activation i growth arrest and apoptosis 10/20/09 Slide 63: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway Adenomatous polyposis coli genes (APC) • Main function is down-regulation of growth-promoting signals Loci found at chr. 5q21 Component of WNT signalling pathway Important function of the APC protein is to down-regulate ß-catenin 10/20/09 • • • Slide 64: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway WNT Signalling Pathway • Major role in controlling cell fate, adhesion, and cell polarity during embryonic development Required for self-renewal of hematopoietic stem cells Signals through cell surface receptors called frizzled (FRZ) 10/20/09 • • Slide 65: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway In Resting Cells: No WNT signallin APC forms g macromolecular complex with ß-catenin, axin, and GSK3ß (destruction complex) Phosphorylation and degradation of ß-catenin No proliferation 10/20/09 No accumulation of ß-catenin in the cytoplasm Slide 66: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway With WNT signallin g Deactivation of destruction complex Increased cytoplasmic levels of ß-catenin Translocation of ßcatenin to the nucleus Forms complex with TCF Cell pfoliferation Activation of c-MYC, cyclin D, and other genes 10/20/09 Slide 67: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway APC mutated or absent Cells behave as if they are under continuous WNT signalling Cell pfoliferation Activation of c-MYC, cyclin D, and other genes No destruction of ß-catenin Translocation of ßcatenin to the nucleus Forms complex with TCF 10/20/09 Slide 68: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway 10/20/09 Slide 69: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway Significance: • Colon tumors normal APC genes with mutations in ß-catenin P no destruction of ß-catenin by APC Mutations in ß-catenin gene present in more than 50% of hepatoblastomas and approx. 20% of hepatocellular carcinoma • 10/20/09 Slide 70: M O L E C U L A R B A S I S Tumor Suppressor Genes: APC/ß-Catenin Pathway Significance: • ß-catenin normally binds to the cytoplasmic tail of E-cadherin maintain intercellular adhesiveness ü Mutation of ß-catenin/E-cadherin axis M loss of contact inhibition r easy disaggregation of cells t favor malignant phenotype ü Mutation of ß-catenin/E-cadherin axis M ß-catenin translocates to nucleus M cell proliferation 10/20/09 Slide 71: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors INK4a/ARF • • Also called CDKN2A gene locus Two protein products: 1. p16/INK4a CDKI d block cyclin D/ CDK2-mediated phosphorylation of RB; crucial for induction of senescence; silenced by hypermethylation of the genes 2. p14/ARF i inhibit MDM2 f prevent destruction of p53 10/20/09 Slide 72: 10/20/09 Slide 73: 10/20/09 Slide 74: 10/20/09 Slide 75: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors TGF-ß • Potent inhibitor of proliferation in most normal epithelial, endothelial, and hematopoietic cells Regulates cellular processes by binding to a serine-threonine kinase complex composed of TGF-ß receptors I and II • 10/20/09 Slide 76: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors Repression of Decrease Cell TGF-ß c-MYC, CDK2, d cycle CDK4, and phosphoarrest cyclins A and rylation of Ligand E RB bindin Activation of the g kinase & phosphorylation of Dimerizati receptor SMADs (Ron of Activate SMADs) R-SMADs receptor transcription enter of genes nucleus (CDKIs p21 Bind to & p15/INK4b) SMAD-4 10/20/09 Slide 77: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors TGF-ß • Can prevent or promote tumor growth depending on the state of other genes in the cell Mutations affecting type II TGF-ß receptor cancer of colon, stomach, endometrium Mutational inactivation of SMAD4 pancreatic cancer 10/20/09 • • Slide 78: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors PTEN (Phosphatase and tensin homologue) • Gene on chr. 10q23 Membrane-associated phosphatase o acts as a brake on the pro-survival/ pro-growth PI3K/AKT pathway u most commonly mutated pathway in human cancer • 10/20/09 Slide 79: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors PTEN (Phosphatase and tensin homologue) • Mutated in Cowden syndrome C autosomal dominant; frequent benign growths (tumors of skin appendages) and increased incidence of epithelial cancers (breast, endometrium, thyroid) 10/20/09 Slide 80: M O L E C U L A R B A S I S Stimulato ry signals Bind to receptor tyrosine kinases (insulin receptor) Phosphoryla tion of PIP2 to PIP3 Inactivati on of PDKI Activation of BAD & MDM2 Cell survival PTEN dephosphor ylate PIP3 to PIP2 Activation of serine/threonine AKT Inactivation of TSC1/TSC2 complex Activation of mTOR 10/20/09 (+) uptake of nutrients for growth and protein synthesis Slide 81: M O L E C U L A R B A S I S 10/20/09 Slide 82: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors NF1 (Neurofibromatosis 1) • Inheritance of one mutant allele r benign neurofibromas and optic nerve glioma i neurofibromatosis type 1 Protein product called neurofibromin • 10/20/09 Slide 83: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors NF1 (Neurofibromatosis 1) Facilitate conversion of active RAS to inactive state RAS always active 10/20/09 Neurofibro min present Inhibit cell proliferatio n Neurofibro min absent Cell proliferati on Slide 84: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors NF2 (Neurofibromatosis 2) • Germline mutation o benign bilateral schwannomas of acoustic nerve r neurofibromatosis type 2 Somatic mutations of both alleles S sporadic meningiomas and ependymomas • 10/20/09 Slide 85: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors NF2 (Neurofibromatosis 2) • Protein product: neurofibromin 2 or merlin o part of SalvadorWarts-Hippo (SWH) tumor suppressor pathway Homologous to red cell membrane cytoskeletal protein • 10/20/09 Slide 86: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors NF2 (Neurofibromatosis 2) Absent merlin Unstable cell-to-cell junctions Disaggregat ion of cells 10/20/09 Loss of contact inhibition Slide 87: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors VHL (von Hippel-Lindau gene) • • • Chromosome 3p VHL protein part of ubiquitin ligase complex t critical substrate is hypoxia-inducible transcription factor 1α (HIF 1α) Germline mutation l hereditary renal cell cancers, retinal angioma, renal cyst, pheochromocytoma, hemangioblastomas of CNS 10/20/09 Slide 88: M O L E C U L A R B A S I S VHL (von Hippel-Lindau gene) Oxyge n presen t Hydroxyla tion of HIF 1α Bind to VHL protein HIF 1α not recognized by VHL Translocat ion of HIF 1α to 10/20/09 nucleus Hypox ia Ubiquitinat ion & proteosom al degradatio n Activation of growth/ angiogenic factors (VEGF, Slide 89: M O L E C U L A R B A S I S 10/20/09 Slide 90: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors WT-1 (Wilms’ Tumor-1 gene) • • • Chromosome 11p13 Protein product a transcriptional activator of genes involved in renal and gonadal differentiation Overexpression f Wilms’ tumor and a variety of adult cancers (leukemias and breast Ca) 10/20/09 Slide 91: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors Patched (PTCH-1 & PTCH-2) • Protein product (PTCH) is a cell membrane protein P functions as receptor for family of proteins called hedgehog Hedgehog/PATCHED pathway regulates TGF-ß, PDGFRA and PDGFRB genes 10/20/09 • Slide 92: M O L E C U L A R B A S I S HSC Ptc – Patched; Hh – hedgehog; Smo – smoothened; Ci – cubitus interruptus (transcription factor); Fu – fused (serine/threonine kinase); Cos2 – costal 2 (kinesin-like molecule); PKA – protein kinase A; CK 1 – protein 10/20/09 kinase CK 1; Sufu – suppressor of fused; GSK3 – Slide 93: M O L E C U L A R B A S I S Other Genes That Function as Tumor Suppressors Patched (PTCH-1 & PTCH-2) • Mutations in PTCH T Gorlin synd. G nevoid basal carcinoma synd. PTCH mutations present in 20% to 50% of sporadic cases of basal cell carcinoma 50% of mutations caused by UV exposure 10/20/09 • • Slide 94: M O L E C U L A R B A S I S 10/20/09 Slide 95: E N D of P A R T 2 10/20/09