L04 Cytoplasmic signalling and cancer

Question 1

What is intracellular signalling?

Answer 1

Set of linked biochemical events that connect a specific biological stimulus with a specific cellular response

Question 2

What are the four properties of intracellular signalling pathways?

Answer 2

Specificity
Transduce signal across membrane into cell
Amplify external signal within the cell
Regulate cellular signals 
(STAR)

Question 3

What are the five layers of the signalling pathway?

Answer 3

Signal
Receptor
Transduction
Intracellular targets
Cellular response 

=(CRITTRS)

Question 4

Examples of extracellular signals?

Answer 4

Tastants
Odorants
Photons
Peptides
Lipids
Amino acids derivatives e.g. epinephrine, histamine
Nucleotides e.g. ATP
Gases

=(TOPPLANG)

Question 5

What is a ligand?

Answer 5

A molecule that binds to a specific site on another molecule, usually a receptor protein

Question 6

Examples of cell signalling outcomes?

Answer 6

Changes in gene expression
Regulate translation
Regulate cell cycle
Cell migration
Initiate angiogenesis
Initiate apoptosis

Question 7

What are the three important signalling pathways in cancer?

Answer 7

Proliferation (mitogenesis)
Survival (anti-apoptosis)
Motility (invasion and metastasis)

=(MAIM)

Question 8

What is mitogenesis?

Answer 8

Uncontrolled, continuous cell division leading to increased cell number and thus formation of a tumour mass

Question 9

What is anti-apoptosis?

Answer 9

Loss of a cell’s programmed ability to commit suicide after a given number of cell divisions and/or after losing contact with its substrate

Question 10

What is invasion and metastasis?

Answer 10

The ability of a cell to move from the primary tumour mass, into the bloodstream, or the lymph system and out again at a secondary site

Question 11

Three types of mitogenic agonists?

Answer 11

Polypeptide growth factors
Peptides and lipids
Cytokines

Question 12

Example of a polypeptide growth factor?

Answer 12

EGF (epithelial)
VEGF (vascular endothelial)
PDGF (platelet driven)

Question 13

Three types of cell surface receptors?

Answer 13

Ligand gated ion channel
GPCRs
Enzyme-linked receptor e.g. GF receptor

Question 14

Three steps of Growth Factor receptor signalling?

Answer 14

Dimerisation in extracellular space
Binding of receptor to signal
Activation of receptor

=(DEBRA)

Question 15

What is Ras?

Answer 15

Oncogene

Question 16

What does Raf recognise?

Answer 16

Ras-GTP

Question 17

Define apoptosis.

Answer 17

Mechanism that allows a cell to self-destruct when stimulated by the appropriate trigger, which may result when a cell is no longer needed or becomes a threat to the organism’s health

Question 18

Define anoikis.

Answer 18

Form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding ECM

Question 19

Define necrosis.

Answer 19

Form of cell death that results from injury, disease, or other pathological state

Question 20

Types of survival factors?

Answer 20

Mitogens
Integrins
Survival factors

Question 21

What are integrins?

Answer 21

Cell-ECM adhesion factors
Heterdimers of alpha and beta subunits that bind to the EC, control cell survival, proliferation and cytoskeletal structure

Question 22

What is the kinase that converts PIP2 to PIP3?

Answer 22

PI3K

Question 23

What is the phosphatase that converts PIP3 to PIP2?

Answer 23

PTEN

Question 24

What is PTEN?

Answer 24

Phosphatase and tumour suppressor

Question 25

What goes wrong to initiate cancer development?

Answer 25

Protein mutation (activating) Protein mutation (inactivating/deleting) Protein addition Protein amplification

Question 26

How are signals transduced from one protein to another signalling pathway?

Answer 26

Generation of intracellular signals

Question 27

Types of intracellular signals?

Answer 27

``` Sugars Ions Gases Nucleotides Lipids ``` =(SIGNL)

Question 28

What is required of second messengers?

Answer 28

Rapidly generated, diffusable, and removed

Question 29

What is changed to generate intracellular signals?

Answer 29

Localisation of a component Enzyme Activity of protein Concentration of an intracellular ligand =(LEAC)

Question 30

When EGF binds to EGFR, what happens to Grb2?

Answer 30

Grb2 gets phosphorylated, which activates SOS to convert Ras-GDP to Ras-GTP, which in turn is recognised by Raf protein and proliferation ensues

Question 31

What type of receptor is EGFR?

Answer 31

Receptor tyrosine kinase

Question 32

Significance of HER2?

Answer 32

Overexpression leads to constitutive signalling | HER2 positive breast cancer shortens survival

Question 33

What is Herceptin?

Answer 33

Humanized anti-HER2 antibody; high affinity and specificity

Question 34

What is Imatinib (/Gleevec)?

Answer 34

Abl-specific tyrosine kinase inhibitor; it blocks the ATP binding site of Abl kinase. Has broad spectrum anti-proliferative activity against haematological and solid tumour cell lines

Question 35

Side fx of Imatinib?

Answer 35

Hepatic toxicity | Neutropenia at high doses

Question 36

How might there be resistance to Imatinib?

Answer 36

Mutations in kinase domain Amplification of BCR-Abl fusion gene Multidrug resistance