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Biochem of Cancer Tumor Suppressors.Pptx 4/6/15 Biochemistry of Cancer Tumor Suppressor Genes 1 4/6/15 Tumor Suppressor Genes Fusion Expt • Recessive phenotype • Hybrid cells – – Oncogenes (viral or cellular) dominate a phenotype – i.e. acFvaon of cancer like behaviors. Ras, Myc, Erb heterokaryons eventually – all sFmulate aggressive growth, moFlity, invasion, only one set (mixed) of migraon and tumor growth chromosomes will remain – These are dominant cancer phenotypes • Tumor cells (expected – First hint of a different sort of cancer gene came with dominant allele) did was fusogenic experiments using PEG or specific virus recessive • Indicang another gene/ • NIH 3T3 and monkey kidney cells fused allele was involved. Loss of with proteins expressed by Sendai virus which was only way to detect. Thus recessive.. Sort of… Simple Definion • Tumor suppressor gene (aka anF-oncogene) stops cell growth protecFng cell from cancer like behavior – Act in recessive behavior giving rise to the “two hit” hypothesis. Loss of both genes must take place before phenomenon is observed. – ReFnoblastoma is a classic example of tumor suppressor genes – Some tumor suppressor genes are not recessive but “dominant negave” Mutaon of one gene copy will prevent normal funcFon. Typically a dimer were mutaon allows dimer to form with wild-type protein but block its effect– p53 is an example 2 4/6/15 ReFnoblasoma • Tumor arising in youth very rare – 1 in 20,000. Occurs early. Tumor within the eye causing blindness. • Most treatment by radiaon or removal of the eye • Two forms. – Those with no family history (unilateral) have tumors in one eye and is considered sporadic. No further risk of other tumors later – Familial form (bilateral) o]en have tumors in both eyes and have greater risk of other tumors forming at distal sites KineFcs of age and frequency • Suggest unilateral result from a single event while sporac tumors require two random mutaons/ events. • Lead to speculaon of an unknown gene called Rb. 3 4/6/15 Rb funcon Loss of Heterozygosity (LOH) • ReFnoblastoma – RB1 gene expressing pRB. • Several tumor suppressors display LOH • Phosphorlyated transcripFon REPRESSOR that • Removal of remaining TS gene by blocks Go-G1 transiFon. recombinaon events during mitosis • Binds and blocks E2F TF which drives DNA • Small geneFc populaon interbreeding replicaon. E2F is target of several oncogenes (endogamy) leads to LOH Other mechanisms of TS loss • Hypermethylaon of cytosine bases. • CpG (C is methylated following a G base) such CpG islands occur in some promoter regions • CH3-cytosine represses TF and Promoter binding but is reversible. • Mechanism (not the enzyme, but control of methylaon) is largely unclear at this Fme. • 70% of genes have CpG islands. 4 4/6/15 • Example of mulFple TS genes with hypermethylaon in some cancers. • Not all TS are methylated • Height of each bar indicates the proporFon of tumors of a type of tumor with hypermethylaon TS Genes APC – Colon Cancer APC Familial Adenomatous Polyposis • Those with family history with parent or sibling • Colon cancers – longest part of the intesFne. with disease has nearly a three fold greater risk of Most are secreFng mucus cell cancers colorectal cancer. Less than 1% of CR Cancer (adenocarcinomas) have FAP • O]en combined with rectal cancer (last • FAP paents display a carpet of polyps several inches of intesFne) for colorectal cancer • Most CR cancers show no or lidle familial associaon ~5% are familial adenomatous polyposis (FAP) 5 4/6/15 Your Colon • Colonic crypt cells provide new cells as stem cells at the bodom of the deep “cave” divide – retaining one daughter stem cell and a second daughter cell that is differenFated • DifferenFated cells migrates to luminal surface (epithelial cells) of the colon to secrete mucus and serve as the lining of the gut • Most cells die within 3-4 days. • Cells at surface face harsh environment of mutagenic compounds from diet, radicals from oxidaon and other harsh typical condiFons of intesFne (pH ect...) • Mutagens occur o]en in these cells but • Cypts – shown with white arrowhead quickly die before progressing to cancer cells • Epithelial cells migrate though small hole at – thus only cancers that can happen will stop the out-migraon of epithelial cells where the top of crypt (narrow black arrow) addiFonal lesions can induce proliferaon • Broad white arrow points to protruding and tumor formaon can take place… APC daughter cells Wild-type • Stromal cells (fibroblasts, inflammatory cells and Wnt, catenin, APC & Wnt and ß-catenin Signaling endothelial cells) secrete growth factors, cytokines and other agonists including Wnt, to cancer • ß-catenin has several induce cell growth. signaling roles – one is • The paracrine stromal cell signaling acFvates Wnt via Wnt signaling in dividing stem and differenFated cells • Wnt – extracellular • Wnt increases ß-catenin and decreases APC GPCR 350-400 aa protein agonist. Family of • ß-catenin binds TF Tcf/Lef leading to increased conserved proliferaon and decreased differenFaon (more glycoproteins that are stem cell like) also palmitoylated for • APC – causes the degradaon of ß-catenin secreFon and • Luminal cells are not sFmulated by stromal cells, membrane associaon less Wnt, -> less ß-catenin and more APC (which • Wnt binds to GPCR also decreases ß-catenin). Leading to loss of proliferaon (cell cycle) and more differenFated class (Fz/frizzled family (less stem cell/cancer like) behavior and cell receptors) AND must death bind to co-receptor Cancer lipoportein receptor- • Tumor suppressor APC mutaons do not reduce related protein (LRP). ß-catenin slowing migraon and causing greater TOGETHER, Wnt proliferaon and less differenFaon. Allow signals in two disFnct build up of addiFonal mutaons for full pathways – Canonical development of tumor mass – mulFple polyps and noncanonical 6 4/6/15 Wnt and ß-catenin Signaling Canonical Wnt Signaling Non-canonical Wnt Signaling • ß-catenin is phosphorylated and In biochemistry, a pathway or signaling method that is thought to be general and targeted for proteolysis in the understood is considered canonical (i.e. absence of Wnt GF-ERK signaling pathway) • … or in the absence of Wnt, ß- • Wnt signaling is much more important than cancer – but is our catenin is not phosphorylated and focus here remains intact and binds to TF • Canonical pathway – lack of wnt factors leads to loss of ß-cat • GSK3B phosphorylaon of ß- • Canonical Wnt signaling remains without LRP phosphorylaon (most catenin targets b-cat for GSK3 and some Casein kinase 1 ubiquiFnaon and ulFmately (CK1) proteolysis • Frizzled (Fz) is a GPCR acFvates • Half life of ß-catenin is about 20 min Dishevelled (Dsh) which is also – w/phosphorylaon; 1-2 hours capable of being phosphorylated • Axin is a scaffolding protein (also aer phosphosphorylaon. Thus another tumor suppressor) unless GSK3B acFon is blocked coordinates binding of kinases, small there will be very lidle ß-catenin in G protein regulators, ß-cat and ubiquiFn ligase (for ß-cat cytoplasm degradaon). • Together Wnt signaling and ß- • GSK & CK1 phosphorylate Axin and Catenin are involved in a large APC -> Fghter binding of Axin and APC with ß-catenin leading to more number of cell regulaon events ß-cat phosphorylaon and and loss of control leads to many degradaon diseases/disorders • Wtx Wilms tumor suppressor gene • APC in polyps, high Wnt signaling in on X chromosome) role is unclear • APC role is complicated in both several breast cancers signaling pathways APC • Adenomatous polyposis coli gene – tumor suppressor protein encoded by APC gene. • Large protein that complexes with axin and conducn to bring ß-canin to GSK3B and CK1. • APC forms oligomers, an armadillo region (ARM - small repeats forming hairpin turns and helixes) and binding sites for other proteins. • Dimers of APC are criFcal for APC funcFon. APC mutants can bind and block wild-type APC (dominant tumor suppressor funcon) • APC forms mulFprotein complex to phosphorylate ß-catenin. • In Wnt acFvated crypt cells – APC is not expressed leaving ß-cantenin un- degraded for TF binding/acFvaon 7 4/6/15 Tumor Suppressor APC Gene InacFvaon • Most common mutaons are mapped to regulatory sites of APC protein -> truncated APC or non-protein binding APC • Some colon polyps show hypermethylaon in APC gene decreasing APC expression • Results in accumulaon of ß-catenin in 90% of sporadic colon carcinomas • Exact role is not as clear as this but mutaons help our understanding of role as a suppressor 8 .
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