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22.CANCER AS A GENETIC DISEASE
A.
B.
Wild-type embryo in which the bright spots are cells carrying out a genetic program to
die (apoptosis).
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 and the control of cell number:
An overview
: 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
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
Cyclins and cyclin-dependent protein kinases
- 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
The target proteins for CDK phosphorylation
are determined by the associated cyclin
Cell proliferation machinery
Cyclins and cyclin-dependent protein kinases
- 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
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
Yeasts : genetic models for the cell cycle
The cell cycle of the budding yeast Saccharomyces cerevisiae (different bud sizes)
•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.
2.
3.
Fragmentation of the DNA of the chromosomes
disruption of organelle structure
loss of normal cell shape (apoptotic cells become spherical)
The cells break up into small cell fragments called apoptotic bodies that are
phagocytosed (ㅣiterally, eaten up) by motile scavenger cells
Machinery for programmed cell death
Caspases
- The engines of self-destruction are a series of enzymes called caspases (cysteinecontaining 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.
Machinery for programmed cell death
Caspases
Initiator caspases are cleaved
In response to activation signals
The role of executioner caspases in
apoptosis, executioner caspases
enzymatically cut the target proteins.
Machinery for programmed cell death
The nematode Caenorhabditis elegans:
a genetic model for programmed cell death
mutant analysis ; identification of ced-3 (caspase)
Examples of programmed cell death in the development of C. elegans.
Hatching of the egg
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
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
Intracellular signals
1. The cell cycle: negative intracellular controls
activation of proteins that can inhibit the protein kinase activity of CDK-cyclin
complexes
“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.
Controlling the cell-proliferation
and death machinery
Intracellular signals
- 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
P21 binds to the CDK-cyclin complex
and inhibits its protein kinase enzymatic activity
P53 is able to activate p21
G1-to-S checkpoint block
The cell cycle: negative intracellular controls
-Fail-safe systems (checkpoints) ensure that the cell cycle does not progress
until the cell is competent.
Controlling the cell-proliferation
and death machinery
Intracellular signals
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.
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)
<The roads to ruin: two major apoptotic pathways in mammalian cells>
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
Extracellular signals
Example : signal transduction of
Receptor tyrosine kinase
RTK autophophorylation
Binding of
adaptor proteins
Interaction with
other proteins
Phosphorylation of
substrate proteins
Conformational
changes
Induction of signal transduction activity
Controlling the cell-proliferation
and death machinery
Extracellular signals
An example : a pathway for RTK signaling
Quite often, the next step in propagating the
signal is to activate a G-protein
G-protein cycle
Sos ; adapter protein of RTK
Phosphorylation of transcription factors
Regulation of gene expression
Controlling the cell-proliferation
and death machinery
Extracellular signals
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
An integrated view of the control of cell numbers
The ways to modulate cell number  control cell proliferation and self-destruction
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
<normal cell>
Contact inhibition
<cells transformed with
Rous sarcoma virus>
Cancer: the genetics of aberrant cell control
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)
<The multistep progression to malignancy in cancers of the colon and brain>
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.
2.
3.
Point mutations
Loss of protein domains
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
<The major pathways that are mutated
to contribute to cancer formation
and progression>
Cancer research in the genomic analysis era
Survey the expression levels of all gene products during the formation
and progression of a particular type of tumor  transcriptome, proteome