Cancer Remedial

8/8/2019 Cancer Remedial

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MOLECULAR BASIS OF CANCER

Learning Outcomes:

1. How Uncontrolled Cell Division leads to Cancer

2. Causes

3. Functions of COMMON Proto-Oncogenes

i. How its GAIN-OF-FUNCTION mutation contributes to Cancer

4. Functions of COMMON Tumour Suppressor Genes

i. LOSS-OF-FUNCTION mutation contributes to Cancer

5. Describe development of Cancer as a MULTI-STEP PROCESS

HWA CHONG INSTITUTION / 2010 JC1 H2 BIOLOGY / LEE TUNG LIN / MOLECULAR BIOLOGY OF CANCER

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A coronal CT scan showing malignant cancer of the lung sac.Retrieved fromhtt ://en.wiki edia.or /wiki/File:Tumor Mesothelioma2 le end.


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DEFINITION


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CANCER

Single/ Group of Abnormal

Cell(s)

Rate of Cell Proliferation > Rate

of Cell Death

Uncontrolled Cell Division

TUMOUR

INVADES

Surrounding TissuesMETASTASIS

Originates From

Exhibiting

Leading to

Results in

(Neoplasm)

- Form Secondary Tumours

DEATH

Left Untreated

Accumulation of anumber of randomgenetic mutations


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PROTO-ONCOGENES

Encode Gene Products (Proteins) that promote CELL PROLIFERATION.

TYPES OF GENE PRODUCTS (PROTO-ONCOGENES)TYPE OF GENE PRODUCT FUNCTION EXAMPLES

Growth Factors Molecules which stimulate CellGrowth and Division (Hormones or

Proteins)

Eg. Erythropoietin induces RedBlood Cell Precursors to divide.

GF Receptors Bind Growth Factors-On Extracellular layer of the Cell

Surface Membrane

Eg. Fibroblast Growth Factor(FGF) Receptors for WoundHealing, Angiogenesis,Embryonic Development

Protein Kinases Intracellular Molecules

- Signals Cell to perform specificactions (KIV Cell Signalling)

Eg. Cyclin-Dependent Kinases

in cell-cycle control system

Transcription Factors Promoting Expression of Cell-Division Cycle Genes (cdc genes)

Eg. Myc gene gives a productwhich activates many genes- Its Oncogene is found in manycancers, such as Burkitt'sLymphoma

Survival Factors Prevents Cells from undergoingApoptosis

Eg. X-linked inhibitor OfApoptosis Protein (XIAP)- Suppresses activators ofApoptosis- Its mutant form can result inthe development of lungcancer.


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GAIN-OF-FUNCTION MUTATION Confer new or enhanced activity on gene product

1. POINT MUTATION Nucleotide substitution in Genetic Sequence

Primary Structure of Polypeptide altered Hence, tertiary structure too

3D Conformation of protein altered Giving a HYPERACTIVE product

Control regions Eg. Increased number of Proximal Promoter Elements/Enhancers

Increased Transcription of Gene

Increased Production of protein.

2. GENE AMPLIFICATION Increased copies of Proto-Oncogene

Increased expression of gene product Stimulating Cell Proliferation

3. CHROMOSOMAL REARRANGEMENTS Transolocations/ Inversions/ Deletions

Expression of Gene product Increases/ More Hyperactive product formed

Transposition Proto-Oncogene flanked by 2 transposons

Relocated to a more active promoter

Increased production of Proto-Oncogenic Protein

4. GENE MUTATION

Deletions/Insertions within coding region of gene

Frameshift Mutation

Primary Structure altered Hence changing the 3D Conformation of protein Hyperactive protein produced

5. INSERTIONAL MUTAGENESIS

Retrovirus integrates their genetic material in the region of a proto-oncogene

Alters coding region of gene Resulting in an abnormal protein

Regulatory regions of gene Over-expression of gene

ONCOGENE Promotes Uncontrolled Cell Division

Only the mutation of 1 allele is needed (Dominant)


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EXAMPLE: ras PROTEIN Coded for by a PROTO-ONCOGENE

Found on the intracellular side of the Cell Surface Membrane

Inactive Form GTP bound to it

Function:

1. Growth factor binds to receptor2. Stimulates removal of GDP from ras protein3. Ras Protein takes up a GTP molecule 'Active' Form4. Activates proteins (Protein Kinases) involved in Signal Transduction Pathways5. Signal reaches nucleus Expression of cell-division-cycle genes6. Cell Proliferation

However:1. Normal Ras Protein hydrolyses its GTP to GDP Inactive form2. Unable to stimulate more downstream signalling pathways3. Cell division kept in control.

RAS ONCOGENE

Produces Constitutively-active Ras Protein (Always in 'Active' Form GTP Bound)

Unable to hydrolyse bound GTP to GDP

Increases concentration of ras-GTP complex

In absence of Growth Factor,

Continues to switch on signal transduction pathways

Increase cell signalling, and hence transcription of cell-division-cycle genes

Excessive Cell Division Contributes to Cancer.


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Retrieved from http://courses.washington.edu/conj/gprotein/monomericgp.htm


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TUMOUR-SUPPRESSOR GENES Codes for a protein

(1) Represses Cell Division due to inappropriate progression within cycle(2) And/Or Promotes APOPTOSIS

Inhibits Excessive CELL GROWTH and PROLIFERATION

FUNCTIONS OF TUMOUR SUPPRESSOR GENE PRODUCTS

1 Repress Genes needed for Cell Growth and Division Progression

2Takes part in cell-division repressing Signal Transduction pathways

- Prevents continuation of Cell Division

3 DNA Damaged -- Cell Cycle is arrested

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Initiates DNA repair mechanisms- Mutation of DNA repair proteins lead to more DNA damage- Leads to increased inactivation of other Tumour Suppressor Genes

- Leads to increased activation of Oncogenes- Contributes to Cancer

5 DNA damage not repaired APOPTOSIS initiated

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Known as Metastasis Suppressors- Maintain Cell to Cell Adhesion

1. Prevents tumour cells from dispersing2. Block loss ofContact Inhibition

- Cell growth arrested when 2 or more cells come into contact3. Prevents METASTASIS


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LOSS OF FUNCTION MUTATIONBoth copies of Tumour Suppressor Gene mutated non-functional or less active Gene

Product formed

1. POINT MUTATION Nucleotide substitution in Genetic Sequence

Primary Structure of Polypeptide altered Hence, tertiary structure too 3D Conformation of protein altered

Giving a NON-Functional protein

Control Regions Eg. Increased number of Silencers

Decrease Transcription of Gene

Less Protein formed.

2. CHROMOSOMAL REARRANGEMENTS Transolocations/ Inversions/ Deletions

Eg. Small Portion of gene inverted Remaining portion still intact

Primary Structure of Gene altered Change in tertiary structure Non-fuctional gene product formed

3. GENE MUTATION

Deletions/Insertions within coding region of gene

Frameshift Mutation

Primary Structure altered Hence changing the 3D Conformation of protein

Non-Function Protein produced

4. EPIGENETIC CHANGES

Changes outside of the Coding region eg. Methylation of the promoters of both alleles of the Tumour Suppressor Gene

Decreased Transcription of Gene

Gene Product not synthesized

MUTANT CELL1. Uncontrolled Cell Division2. Evades Apoptosis (Cell Death decreases)3. Genetic Instability Susceptible to more cancer-causing mutations with subsequent

cell divisions


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EXAMPLE: p53 Transcription Factor

Activated in response to

Oncogenic Activators

DNA Damage

Oxygen Deprivation (Hypoxia)

Exposure to UV rays

FUNCTIONS (in response to triggers)

1. p53 binds to DNA control elements

Promotes expression of genes which inhibit the Cell Cycle

Holds cell cycle at G1 Checkpoint on recognising damaged DNA

DNA not replicated and time is given for damage to be repaired

2. Stimulates Expression of genes which initiate the DNA REPAIR MECHANISM

3. APOPTOSIS initiated if damage is irreversible.

4. Acts as a negative regulatorof gene expression

Interacts with general transcription factors

Decreases expression of other genes eg. Cell-Division-Cycle genes

Prevents cell from dividing.

5. Inhibits Angiogenesis

NON-FUNCTIONAL p53 PROTEIN


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Loss Of Function Mutation


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CANCER A MULTI-STEP PROCESS


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Retrieved from http://en.wikipedia.org/wiki/File:P53_pathways.jpg

SINGLE ABNORMAL CELL

Accumulation of Mutations along its lineage- Requires more than a dozen independent

mutations- Formation of a Tumour

- Activation of a number of proto-oncogenes toONCOGENES

-Inactivation/Loss of Tumour Suppressor Genes

Activation of Telomerases- Cells divide- However, telomeres of the chromosomes donot shorten due to presence of telomerase- Or Cells continue dividing despite extremelyshort telomeres

- Consequently, telomerase is activated- Cells have enough chromosomal stability tosurvive- Prevents cells from reaching Hayflick Limit- Do not enterReplicative Cell Senescence- Cell Proliferation continues

Hayflick Limit: Number of times a cell population dividesbefore stopping due to telomeres reaching critical length

Replicative Cell Senescence: A period where cells stopdividing and eventually undergo Apoptosis

Telomerase: Enzyme which catalyses the elongation of thetelomeres.


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GROWTH OF PRIMARY TUMOUR- Uncontrolled Cell Division- Rate of Cell Proliferation > Rate of Cell Death- Tumour cells lose resemblance to normal cells- Change in size and shape- Distorting tissue

ANGIOGENESIS- Formation of new blood vessels around tumour- Increased Circulatory Supply ofOxygen andNutrients- Remove Waste Products from tumour- Growth of Tumour

METASTASIS- Tumour grows- Invade surrounding tissues- Penetrate walls of lymphatic and blood vessels- Cancer cells enter bloodstream- Travel to distant sites of the body- ESTABLISH SECONDARY TUMOURS- Angiogenesis occurs too- Organ Function deteriorates

- Cancer cells grow and proliferate- Competing for space and nutrients with normalcells- Compression of vital organs occur

- Normal tissues starved of nutrients- Cancer cells replace healthy cells in organ

DEATH


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METASTASIS

ANGIOGENESIS


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Cancer Remedial

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