🧬Cancer and signalling

Define what is meant by cell signalling

Cell signalling is the process which cells communicate with other cells

Why is cell signalling important in medicine

It allows us to understand signalling pathway and directly know treatments for when they go wrong

List types of chemical stimuli

Neurotransmitters

Hormones

Growth factors

Cytokines

Odorants and tastants

Ions

List types of abiotic stimuli

Gravity, pH, oxygen levels, osmolarity

List physical stimuli

Mechanical strength

Temperature

Light

Sound waves

List biotic stimuli

Pathogen associated molcules such as bacteria, viruses

List electrical stimuli

Change in membrane potential

List the different types of signals

Autocrine

Endocrine

Paracrine

Juxtacrine

Synaptic

Outline autocrine signalling

The cell releases signalling molecules which bind the receptors on the same cell surface, triggering response in the same cell

Outline paracrine signals

A cell releases signalling molecules which can move and bind to the receptor on nearby cell surfaces

Outline juxtacrine signals

Membrane bound signalling molecule of one cell binds directly to a plasma membrane receptor of another cell

Outline endocrine signals

Cells produce a signal into the blood stream which can disperse all over the body, normally hormones

Outline synaptic signals

Nerve impulse is triggered and the signalling molecule moves along the axon into the synaptic cleft and binds to a receptor on the post synaptic membrane, this can cause a change in activity of the cell or neuron.

What are the three stages of cell signalling

Reception

Transduction

Response

Reception - what does it entail

The target cell detects the signalling molecule as it is bound to the receptor protein

Transduction - what does it entail

the signal is converted into a form which can be used to produce a specific cellular response

Response - what does it entail

Any cellular activity

What are the two types of receptor

Intracellular and plasma membrane

Intracellular receptors - how do they work, example

Steroid and thyroid hormone

They bind to the steroid and thyroid receptors, this creates the hormone receptor complex which can move to the nucleus, where it acts as a transcription factor and can influence gene expression

eg EGF

Structure of intracellular receptor

Monomeric structure with ligand and DNA binding domains

Structure of ligand gated ion channel

Oligomeric assembly of subunits surrounding central pore. It has a binding domain, crosses membrane 4 or 5 times

Structure of GPCR

Monomeric or obligomeric assembly of subunits compromising seven transmembrane helices with intracellular G protein coupling domain.

Structure of Kinase linked receptors

Single transmembrane helix linking extracellular receptor binding domain to intracellular kinase catalytic domain, crosses the membrane once

Ligand gated ion channel - example, coupling, effector

Effector - ion channel

Coupling - direct

Eg - Ach receptor, GABA receptor

GPCR - example, coupling, effector

Effector - channel or enzyme

Coupling - G protein

Eg - odorant receptors, slow transmitters

Kinase linked receptor - example, coupling, effector

Effector - protein kinases

Coupling - direct

Eg - Insulin, Growth factors, cytokine receptors

How is a signal passed on

Multistep pathway

The activated receptor activates a protein, which activates another protein and so on until a response is made.

This is done since at each step the signal is transduced into a different form = shape change in a protein and info is passed on. Amplification of the signal, opportunities for coordination and regulation

Kinases and Phosphotases

Kinase - aid the addition of a phosphate group to a protein, often activating the protein.

Phosphotase - aids the removal of a phosphate group from a protein, often inactivating the protein.

Second and first messengers

The first messenger - the signalling molecule that binds to receptor

The secondary messenger - participate in signal pathways of both GPCR and kinase linked receptors.

What is cAMP and IP3

A secondary messenger

GPCR and cAMP pathway

Ligand binding causes the G protein to be activated.

G protein causes the activation of adenylate cyclase.

Adenylate cyclase catalyses the transition of ATP to cAMP.

Increase in cAMP triggers the activation of protein kinase A.

Protein kinase A causes a phosphorylation cascade.

Causes a response

GPCR and IP3

Ligand binding causes the G protein to be activated. The activated G protein activates the phospholipase C, which cleaves PIP2 into DAG and IP3. IP3 migrates to the ER where it binds to the IP3-calcium channel, this allows Ca ions to move out of the ER and into the cytosol. The increase of Ca ions in the cytosol causes the activation of proteins.

EGF and the outcomes of signalling and the molecules included

Cell division - Ras, Raf, MEK, ERK1/2

Cell growth and survival - PI3K, AKT, mTORC1

Cell migration - PLC, RAC

What type of output response is cell division, migration, growth and survival

Nuclear response - activation of transcription factors in the nucleus that led to protein synthesis.

What type of output response is muscle contraction and relaxation

Cytoplasmic response - modulation of proteins activity in the cytoplasm

Ach - signal molecules and response

Muscle contraction - PLC, PIP2, IP3, Ca ion

Epi - signalling molecules and action

Muscle relaxation - G protein, adenylate cyclase, cAMP increase, PKA

How is fine tune of the response achieved

Multistep cascade: amplification of the signalling, fine regulation of activation of relay molecules, coordination and integration with other signalling pathways

Involvement of scaffolding proteins

Termination of the signalling

Mechanism of signal termination

Binding of signalling molcules is reversible

Activation of some receptors is followed by receptor internalisation

Relay molecules return to their inactive forms - dephosphorylation of protein kinase

Signal molecules are inactivated via post translational modification

Signal molecules reuptake

Importance of signal termination

Ensures cells respond appropriately to stimuli and maintain a stable internal environment

It prevents diseases - dysregulation of signal termination can lead to various disease such as cancer and neurological disorders

Specificity - signal termination mechanisms can also contribute to the specificity of cellular responses by ensuring that the appropriate signalling pathways are activated and deactivated in a timely manner.

Define hyperplasia

Increase in the number of cells

Define hypertrophy

Increase in cell size

Define atrophy

Decrease in cell size or cell number

Define metaplasia

Cells can change from one cell type into another eg oesophagus epithelia into glandular epithelia known as Barretts syndrome.

Define Aplasia

failure of cell production is embryogenesis

Define hypoplasia

Decrease in cell production during embryogenesis.

Define apoptosis

Programmed cell death

Define necrosis

Uncontrolled cell death

Define inflammation

An inflammatory response in reaction to cell death

Define neoplasia

body tries to fix level of cell death and causes mutations

List features of benign disease

Localised

Well encapsulated

Slow growing

Resemble the tissue of origin

Regular nuclei

Are mitoses

Damage at the local level

Define dysplasia

abnormal/atypical cells due to a failure of differentiation

How can we decide the degree of a tissue

Architecture - disordered architecture so a loss of normal structure

Disordered cellular features (cellular atypia) - pleomorphic nuclei (irregular and variable in size) and mitotic figures (atypical or typical)

List features of malignancy

Invasive

Can metastasise

Grows fast

May not resemble the tissue of origin

Shows features of dysplasia

Damage at local or distant sites

Define metastasis

the invasive neoplasm spreads to other areas of the body and can do this through lymphatics, blood and body cavities

What is cancer of unknown primary

When we have found a secondary site but are unsure where it originally came from

Define neoplasia

An excessive, irreversible, uncontrolled cell growth which still persists even after the stimuli is withdrawn.

Is neoplasia the same as a tumour

A tumour is a swelling or a lump.

Not all neoplasias are guaranteed to cause swelling or a lump eg leukaemia.

What does it mean is an individual is HER2 positive and what is a treatment of this

They produce excessive HER2 and have HER2 breast cancer

Herceptin - this specifically targets HER2 and this is why it is crucial to know the cell cycle in order to target treatments.

What is immunohistochemistry

Technique which allows us to see where certain proteins are expressed within the cell and in roughly what quantities they are expressed.

Define grading

How closely does the neoplasm correspond with the normal cells for that tissue

Define staging

How far has the neoplasm spread throughout the body

TNM classification

Tumour - measures local invasion

Node - measures spread to lymph nodes

Metastasis - measures spread to distant tissues.

5 main areas of effect of neoplasms

Local - pain, lump, ulceration, bleeding, obstruction

Metastatic

Systematic - weight loss, feeling unwell, infection

Paraneoplastic - secretion of excess substances

Mental health - depression, anxiety, frustration, hopelessness.

What suffix is typically added to a benign neoplasm

-oma

eg smooth muscle is leiomyoma

What suffix is typically added to a malignant neoplasm

-sarcoma

eg smooth muscle is leiomyosarcoma

What are some exemptions to the benign and malignant suffix rule

Lymphoma - malignant and not benign

Leukaemia

What is MSI

Microsatellite instability

Occurs when there is a failure of the mechanism to repair damaged DNA in the cell cycle

What is an MMR system

A repair system

What happens if there is damage to the MMR system

Damaged DNA can be passed down to new cells and thus can make them prone to the mutations causing cancer, this higher chance of mutation caused by failure of the MMR system is called MSI.

Briefly outline the stages to the cell cycle

G1 - longest

S phase

G2

M phase - shortest

(PPMATCytokinesis)

G1-S = interphase

M phase = M phase

What is G0

A resting state, where the cells are not actively dividing, it is also known as quiescence, sometimes the cells will reenter the cell cycle such as after antigen presentation the clonal expansion of memory cells, sometimes cells will never leave the quiescence stage such as erythrocytes.

What happens in G1

First growth stage

Cells are growing, synthesis of organelles and proteins

Preparing for S phase in response to external environment

Growth factor dependant

What happens in S phase

DNA is synthesised

What happens in G2

Second growth stage, organelles are duplicated and the cell is prepared for mitosis.

What is the first stage of mitosis

Prophase - nucleolus degradation, chromosomes condense and centrioles move to the poles

What is the second stage of mitosis

Prometaphase - Spindle fibres attach to kinetochore at the centromere region of the chromosomes, nuclear membrane disintegrates

What is the third stage of mitosis

Metaphase - spindle fibres line the chromosomes up along the metaphase plate at the equator of the cell

What is the fourth stage of mitosis

Anaphase - chromatids are pulled to opposite poles of the cell and are now called chromosomes in their own respect

What is the fifth stage of mitosis

Telophase - nuclear membrane forms around the new chromosomes, chromosomes decondense, spindle fibres disperse.

What is cytokinesis

Cleavage of the cell, to form two identical daughter cells

What is a cyclin dependant kinase and its function

CDKs respond to environments, they are activated by cyclins and are responsible in the regulation of the cell cycle and allowing cells to progress to the next stage. They can be serine or thyrosine

What are the activators of CDKs

Cyclins

Phosphorylation or dephosphorylation

CKIs (inhibitors)

List some cyclins and the corresponding CDK - where in the cell cycle they effect

Cyclin D - CDK4/6 - G1

Cyclin E - CDK2 - G1/S

Cyclin A - CDK2/1 - S

Cyclin B - CDK1 - M

What is a cyclin and its function

Cyclin is an activator protein which responds to signals to bind to CDKs in order to activate them and allow cells to progress in the cell cycle. They are synthesised and then removed.

What are CKIs and how do they function

Cyclin dependant kinase inhibitors - they are responsible for blocking CDKs and their activity, they do this by acting as a CDK competitive ligand or inactivating the complex.

What are the 3 types of CKI

p21 - CIP

p27 - KIP

p16 - INK

What manages the progression of G2 into the M phase

Cyclin B - CDK1

Cyclin B levels rise in G2

This causes the phosphorylation of things

What can the CDK1-cyclin B complex cause

Nuclear membrane disintegration by lamins

Spindle formation by microtubule associated proteins

Chromosome condensation by condensin histones

Define checkpoint

A checkpoint can be defined as a point in the cell cycle which decided which cells can progress through the cell cycle and which cannot and will halt their progression

What types of things are checkpoints looking out for

External environment (GF)

Internal environment (growth)

DNA damage

Spindle attachment

Replication errors

Chromosome integrity

What are the 4 types of checkpoint

Restriction checkpoint (G1)

DNA damage (G1/S) (G2/M)

Mitotic (M)

What is restriction checkpoint

Restriction checkpoint is found in the G1 phase and is responsible for entrance into S phase, it uses CDK 4/6 and cyclin D.

What determines cell progression

Growth factors - sufficient signal = progression, insufficient signals = halt

What is the gate keeper at the Restriction checkpoint

Retinoblastoma protein

What is the function of Rb and give an example

Rb is a tumour depressor and is responsible for being a gate keeper, it blocks E2F which is a transcription factor in the cell cycle. When Rb proteins are signalled to by growth factors it unblocks the E2F, this then triggers the activation of the transduction pathway causing the binding of cyclin to CDKs which causes phosphorylation to Rb, this allows E2F to be free and cause transcription and gene expression then translation.

Role of Rb, p53 and BRCA1

Rb - blocks entry into the cell cycle which decided

p53 - detects DNA damage

BRCA1 - repairs DNA damage

Outline p53 and give an example of how it works

p53 is a transcription factor, it detects DNA damage. DNA damage > p53 when there is low stress it causes low p21 levels resulting in cell cycle arrest and DNA repair, when there is high stress levels p21 levels are high causing transcription of genes for apoptosis.

What is the spindle assembly checkpoint

This monitors progression of cells from metaphase into anaphase. If chromosomes aren’t attached properly then anaphase is inhibited, if chromosome attachment is sufficient then anaphase will go ahead.

What is found at the DNA damage checkpoints and what are the checkpoints

p53

Checkpoint from G1 to S

Checkpoint from G2 to M