Presentation on theme: "22.CANCER AS A GENETIC DISEASE A.Wild-type embryo in which the bright spots are cells carrying out a genetic program to die (apoptosis). B.Mutant embryo."— Presentation transcript:
22.CANCER AS A GENETIC DISEASE A.Wild-type embryo in which the bright spots are cells carrying out a genetic program to die (apoptosis). B.Mutant embryo in which this genetic program dose not occur.
Cancer and the control of cell number: an overview - machinery of cell proliferation - machinery of cell death - linking cell proliferation and death to the the environment Cell proliferation machinery - cell cycle - cyclin and CDKs - cdk targets - yeast: genetic models for the cell cycle Machinery for programmed cell death - caspases - C. elegans: a genetic model for PCD Controlling the cell-proliferation and death machinery - intracellular signals - extracellular signals Cancer: the genetics of aberrant cell control - how cancer cells differ from normal cells - evidence for the genetic origin of cancers - mutations in cancer cells - classes of oncogenes - classes of tumor-suppressor genes - inheritance of the tumor types - p53: a link b/w the cell cycle and apoptosis - complexities of cancer Cancer research in the genomic analysis era
: Cancer is now clearly understood as a genetic disease of somatic cells. Machinery of cell proliferation The cell division cycle has evolved so that there are checks and balances to prevent a subsequent event from taking place before the prerequisite events have been achieved. (phosphorylation-dephosphorylation system) Machinery of cell death (in multicellular organisms) - balance the numbers of the cell types in their various tissues - eliminate abnormal cells mechanisms have evolved to eliminate certain cells-through a process called programmed cell death or apoptosis Cancer and the control of cell number: An overview
Linking cell proliferation and death to the environment The cell proliferation and cell death machinery must be interconnected t each is activated only under the appropriate environmental circumstances. Intercellular signaling pathways typically consist of several components - activity of many DNA-binding proteins - protein phosphorylation - interactions between proteins and small molecules - interaction between protein subunits Cancer and the control of cell number: An overview
Cell proliferation machinery Cell cycle : There are four main parts to the cell cycle M phase – mitosis G1 phase – The gap period between the end of mitosis and the start of DNA replication S phase – The period during which DNA synthesis occurs G2 phase – The gap period following DNA replication and preceding the initiation of the mitotic prophase The differences in the rate of cell division = the differences in the length of time between entering and exiting G1
Cell proliferation machinery - The engines that drive progression from one step of the cell cycle to the next are a series of protein complexes composed of two subunits - Sequential activation of different CDK-cyclin complexes ultimately controls progression of the cell cycle Cyclins and cyclin-dependent protein kinases The target proteins for CDK phosphorylation are determined by the associated cyclin
- Because different cyclins are present at different phases of the cell cycle, different phases of the cell cycle are characterized by the phosphorylation of different target proteins. - The phosphorylation events are transient and reversible by phosphatases Cell proliferation machinery Cyclins and cyclin-dependent protein kinases
Cell proliferation machinery CDK targets How does the phosphorylation of some target proteins control the cell cycle? phosphorylation activation of certain transcription factors promote the txn of certain genes required for the next stage of the cell cycle * Rb-E2F pathway in mammalian cells - Rb is the target protein of a Cdk2-cyclin A complex - E2F is the transcription factor that Rb regulates.
Cell proliferation machinery The cell cycle of the budding yeast Saccharomyces cerevisiae (different bud sizes) Yeasts : genetic models for the cell cycle cdc (cell division cycle) mutations ts mutation stop growing at a specific time in the cell cycle at restrictive condition Different cdc phenotypes different defects in the machinery required to execute specific events in the progression of the cell cycle
Cell proliferation machinery Yeasts : genetic models for the cell cycle The cell cycle of the fission yeast Schizosaccharomyces pombe (symmetrical fission) The cdc genes identified in genetic screens in these two very different yeasts encode the same set of proteins the cell cycle machinery is identical
Machinery for programmed cell death Apoptosis pathway : In multicellular organisms, systems have evolved to eliminate damaged (and, hence, potentially harmful) cells through a self-destruct and disposal mechanism: programmed cell death, or apoptosis. 1.Fragmentation of the DNA of the chromosomes 2.disruption of organelle structure 3.loss of normal cell shape (apoptotic cells become spherical) The cells break up into small cell fragments called apoptotic bodies that are phagocytosed ( ㅣ iterally, eaten up) by motile scavenger cells
Machinery for programmed cell death Caspases - The engines of self-destruction are a series of enzymes called caspases (cysteine- containing aspartate-specific proteases). -Each caspase is a protein rich in cysteines that, when activated, cleaves certain target proteins at specific aspartate residues in the target polypeptide chains. (initiators & executioners) - In normal cells, each caspase is present in an enzymatically inactive state, called the zymogen form.
Caspases Machinery for programmed cell death The role of executioner caspases in apoptosis, executioner caspases enzymatically cut the target proteins. Initiator caspases are cleaved In response to activation signals
Machinery for programmed cell death Examples of programmed cell death in the development of C. elegans. Nematode ’ s life cycle A cell that undergoes programmed cell death is indicated with a blue X at the end of a branch of a lineage The nematode Caenorhabditis elegans: a genetic model for programmed cell death mutant analysis ; identification of ced-3 (caspase) Hatching of the egg
Controlling the cell-proliferation and death machinery * Engine in cell proliferation or apoptosis ; cyclin-CDK complex or the caspase cascade * Ignition switches: accelerators (positive controls) and brakes (negative controls) a series of modulations of protein activities through protein-protein interactions and protein modifications “checkpoint” system - When DNA is damaged during G1, the CDK activity of CDK-cyclin complexes is inhibited. - The inhibition seems to be mediated by a protein called p53. - Part of the p53 protein recognizes certain kinds of DNA mismatches. Intracellular signals 1. The cell cycle: negative intracellular controls activation of proteins that can inhibit the protein kinase activity of CDK-cyclin complexes
Controlling the cell-proliferation and death machinery P53 is able to activate p21 P21 binds to the CDK-cyclin complex and inhibits its protein kinase enzymatic activity - CDK ’ s target proteins are not phosphorylated - Cell cycle is unable to progress -When the DNA mismatches have been repaired, the drop of p53 levels & a cessation of inhibition G1-to-S checkpoint block The cell cycle: negative intracellular controls Intracellular signals -Fail-safe systems (checkpoints) ensure that the cell cycle does not progress until the cell is competent.
2. The cell cycle: positive intracellular controls When the brake is released, independent signals from within or outside the cell induce a cascade of protein kinases that phosphorylate the appropriate cyclin-CDK complex, thereby activating the complex. Controlling the cell-proliferation and death machinery Intracellular signals 3. Apoptosis: positive intracellular controls The cytochrome c (mitochondrial proteins) - Apaf (apoptotic protease-activating factor) complex binds to and activates the initiator caspase. 4. Apoptosis: negative intracellular controls Apoptosis pathway remains “off” under normal conditions. (Bcl-2,Bcl-x: block the release of cytochrome c from mitochondria)
Controlling the cell-proliferation and death machinery Extracellular signals 1. Mechanisms for cell-to-cell communication Ligands - endocrine signals: long-range - paracrine signals: local - class: hormones, small molecules, & proteins Transmembrane Receptors - protein ligands act as signals by binding to & thereby activating transmenbrane receptor proteins Ligand-receptor complexes initiate chemical signals in the cytoplasm activation of a series of intermediary molecules alteration of transcription factors in nucleus activation or repression of txn of some genes
Controlling the cell-proliferation and death machinery Example : signal transduction of Receptor tyrosine kinase RTK autophophorylation Binding of adaptor proteins Interaction with other proteins Conformational changes Phosphorylation of substrate proteins Induction of signal transduction activity Extracellular signals
Quite often, the next step in propagating the signal is to activate a G-protein G-protein cycle Controlling the cell-proliferation and death machinery Extracellular signals An example : a pathway for RTK signaling Sos ; adapter protein of RTK Phosphorylation of transcription factors Regulation of gene expression
1. Cell-to-cell signaling depends on conformational changes - the binding of ligands to receptors conformational changes ex) conformational change of protein kinase - recycling of the components of the signaling system 2. The cell cycle : positive extracellular controls - mitogens (polypeptide ligands released from a paracrine source) 3. The cell cycle : negative extracellular controls - an example is TGF- TGF- TGF- receptor serine/threonine kinase SMAD phosphorylation block the phosphorylation and inactivation of Rb protein cell cycle inhibition Controlling the cell-proliferation and death machinery Extracellular signals
4. Apoptosis : positive extracellular controls - the command for self-destruction system comes from a neighboring cell ex) immune system - Fas system 6. Apoptosis : negative extracellular controls -survival factors Controlling the cell-proliferation and death machinery Extracellular signals
An integrated view of the control of cell numbers The ways to modulate cell number control cell proliferation and self-destruction Controlling the cell-proliferation and death machinery
Cancer: the genetics of aberrant cell control How cancer cells differ from normal cells Cancer - aggregates of cells, all derived from an initial aberrant founder cell (clonal) - specific phenotypic changes: rapid division rate invasion of new cellular territory high metabolic rate abnormal shape - occurs by the production of multiple mutation in a single cell Contact inhibition
Evidence for the genetic origin of cancers Carcinogenic agents (mutagenic), inheritance pattern of certain cancers Oncogenes : dominant mutant genes that contribute to cancer in animals isolated from tumor viruses Tumors arise from the result of multiple mutation (benign cancerous) Cancer: the genetics of aberrant cell control
Mutations in cancer cells Tumor-promoting mutations 1. Dominant oncogene mutation (gain of function) 2. Recessive tumor suppressor gene mutation (loss of function) How have tumor-promoting mutations been identified? 1. Pedigree analysis technique : molecular markers 2. Cytogenetic analysis : chromosomal translocations deletion of particular chromosomal regions Cancer: the genetics of aberrant cell control
Classes of oncogenes Proto-oncogenes : normal counterparts of oncogenes 1. Positive control of cell cycle 2. Negative regulation of apoptotic pathway Cancer: the genetics of aberrant cell control
Types of oncogene mutations 1.Point mutations 2.Loss of protein domains 3.Gene fusions Point mutations Example : Ras oncoprotein produced by missense mutation Cancer: the genetics of aberrant cell control
Types of oncogene mutations Loss of protein domains Example: v-erbB oncogene (mutated form of an RTK known as the EGFR) Truncated EGFR form is able to dimerize even in the absence of the EGF ligand - Autophosphorylation - Continuously initiate a signal transduction cascade Cancer: the genetics of aberrant cell control
Types of oncogene mutations Gene fusions Example : bcr1-abl fusion in chronic myelogenous leukemia (Philadelphia chromosome) - Bcr1-Abl fusion oncoprotein has an activated protein kinase activity Cancer: the genetics of aberrant cell control
Types of oncogene mutations Gene fusions Example : translocation between chromosoomes 14 and 18 in follicular lymphoma enhancer of Ig genes-bcl2 gene fusion (Bcl2 : negative regulator of apoptosis) - introduction of an enhancer dominant gain-of-function phenotype by misregulation of transcription unit Cancer: the genetics of aberrant cell control
Classes of tumor-suppressor genes 1. Negative regulators of the cell cycle (ex : Rb protein, TGF- signaling pathways) 2. Positive regulators of apoptosis (ex : p53 protein) 3. Act indirectly through a general elevation in the mutation rate Cancer: the genetics of aberrant cell control
Inheritance of the tumor phenotype Retinoblastoma, a cancer of the retina - Hereditary mutation ; germinal - Sporadic mutation ; somatic Cancer: the genetics of aberrant cell control
P53 tumor-suppressor gene : a link between the cell cycle and apoptosis - 50% of human tumors lack a functional p53 gene - p53 : a transcriptional regulator that is activated in response to DNA damage inhibition of cell cycle progression (G1 arrest) induction of apoptosis Complexity of Cancer - Numerous mutations Cancer: the genetics of aberrant cell control
Survey the expression levels of all gene products during the formation and progression of a particular type of tumor transcriptome, proteome Cancer research in the genomic analysis era
Your consent to our cookies if you continue to use this website.