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Mechanisms of Mutagenesis & Carcinogenesis. Jamil Momand, Ph.D. California State University at Los Angeles. Outline (in brief). Introduction Carcinogenesis - a definition Pathways to cancer: overview Oncogenes Tumor suppressor genes Apoptosis Telomerase Angiogenesis Summary.
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Mechanisms of Mutagenesis & Carcinogenesis Jamil Momand, Ph.D. California State University at Los Angeles
Outline (in brief) • Introduction • Carcinogenesis - a definition • Pathways to cancer: overview • Oncogenes • Tumor suppressor genes • Apoptosis • Telomerase • Angiogenesis • Summary
Maintenance of homeostasis • Adult human maintains ~1015 cells • Stem cells undergo ~1012 divisions per day • There is a balance between cell birth and cell death • Random mutations disrupt homeostasis
DNA damage Failure to repair damage Failure to destroy cells with DNA damage Mutation Molecular basis for cancer progression Selection advantage
Example of DNA damage From Bertram, Molecular Aspects of Medicine 21, 2001, 161-223
Chemical Asbestos Arsenic Chromium Polyaromatic hydocarbons dichlorodiphenyl-trichloroethane (DDT) Physical Gamma radiation UV light Radon X-rays Viruses* List of carcinogens
Hereditary form of colon cancer Case 1: Beth M.'s father died of colon cancer, as did her grandmother. Now two of her brothers, both in their 40's, have been diagnosed with colon cancer. Beth, age 37, feels a curse is hanging over her family and is worried about her future and that of her children. Case 2: Paul C. was 35 when his doctor told him the grim news: he had advanced colon cancer. As far as he knew, Paul had no family history of the disease. But after checking, Paul learned that several aunts and uncles had died of colon cancer at an early age. Diagnosis: hereditary nonpolyposis colorectal cancer (HNPCC) Frequency: 1 in 6 colorectal cancer cases Cause of the disease: hMLH1 or hMSH2 mutations. Genes responsible for DNA mismatch repair
From Bertram, Molecular Aspects of Medicine 21, 2001, 161-223
Clonal Nature of Cancer • Cancers are composed of cells that descended from a single cell. • Evidence 1: X-chromosome inactivation • Evidence 2: Ig genes in lymphomas and leukemias are identically rearranged. • Multistage theory of cancer development (Armitage and Doll, 1954)
Viruses and cancer • Viruses account for 15% of all cancers • DNA viruses • Epstein-Barr virus • Human papilloma virus • Hepatitis B virus • RNA viruses • HIV-1 • HTLV-1 • HTLV-2
DNA Damage Protection Repair Cell cycle arrest Apoptosis Necrosis Chemotherapy Radiation therapy Progression Mutation Proliferation Immortality Mutator phenotype Angiogenesis Metastasis Normal Cell Initiatied Cell Cancer Cell Proliferation Mutations Adapted from Bertram, Molecular Aspects of Medicine 21, 2001, 161-223
Amplification Immortal Oncogene Point mutation Proto-oncogene Transformation Translocation Definitions of terms
DNA Methylation and Demethylation-ways to control expression of genes
Oncoprotein pathways http://www.biocarta.com/pathfiles/pdgfPathway.asp
Her2/neu/erbB-2 • This gene was discovered by three different groups. That is why it has three different names. • Its oncogene counterpart is v-erbB-2 • Dr. Slamon (UCLA) described the role of Her2/neu in breast cancer and ovarian cancer. • Overexpression, amplification, rare translocations • No ligand is known
BCR-ABL translocation and expression http://www.kent.k12.wa.us/staff/vhoward/apbio/oncogenes/brc-ablcartoon.gif
STI-571--an inhibitor of BCR-ABL function http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html
PET scanning to show efficacy of STI-571 on tumor metastasis http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html
Design of experiment to clone the first human cellular oncogene (Shi et al., 1979)
What we have learned • Human cellular oncogenes are dominant-acting genes that transform cells and cause tumors in mice. • Activation-abnormality that results in higher than normal level of biochemical activity. • Point mutation • Overexpression • Proto-oncogenes-The wild-type non-cancerous form of the oncogene
How are oncogenes activated? • Point mutation-Eg. K-ras, • Amplification-Eg. N-myc, MDM2, Her2/neu/ErbB2 • Chromosome translocation-Eg. c-myc, bcr-abl • Overexpression due to DNA demethylation
Tumor suppressor genes • Somatic cell hybrids • Knudsen’s hypothesis • Mutations and mechanisms that • lead to tumor suppressor gene • loss of function • RB • p53
Somatic cell hybrids Transformed Cell fusion Normal Harris et al., 1969 Normal
Mechanisms of tumor suppressor gene inactivation • Deletion • Point mutation • Mutation followed by duplication • Loss of heterozygosity • DNA methylation • Post-translational mechanism-binding to DNA viral oncoproteins
http://p53.curie.fr/p53%20site%20version%202.0/p53%20in%20cancer/p53_databaseANAL.htmlhttp://p53.curie.fr/p53%20site%20version%202.0/p53%20in%20cancer/p53_databaseANAL.html
[MDM2/p53] complex (transient) degradation 1. MDM2 p53 Stabilization p53 Latent DNA Repair Transcription 2. GADD45 3. WAF1/CIP1 Cell cycle arrest 4. DNA damage } 5. Other p53 functions Cell Death synthesis n p53 signal transduction pathway
Functional domains of BRCA1 Transcriptional activation Dimerization BRCA1 C-Term. domains NLS Ring finger Proteins that bind BRCA1: BARD1 Rb BRCA2 p300 BAP1 p53 RHA E2F1 Rad51 RNA PolII cMyc Rad50 CREB binding protein
BRCA1 • Mapped to chromosome 17q by Mary Clair King in 1990 • Linkage was also found in ovarian cancer families. • More than 90% of women with germline BRCA1 mutations lose the wild-type allele in breast tumor. • The gene encodes a nuclear phosphoprotein of 220 kD (1863 aa’s) • The mRNA is 5711 bases long • 24 exons, 22 of which is coding
BRCA1 (cont. 1) • BRCA1-deficient ES cells are hypersensitive to oxidative reagents • BRCA1-deficient ES cells are defective in transcription-coupled repair • Expression of BRCA1 leads to p21CIP1/WAF1 upregulation and G1-S cell cycle arrest (is this through p53?) • BRCA1del11 maintain G1-S cell cycle arrest but not G2-M arrest.
