Onco notes

Question 1

Third messengers?

Answer 1

Molecules which transmit messages from outside to inside the nucleus (or vice versa) (aka DNA binding proteins)

Question 2

Another name for juxtacrine signalling?

Answer 2

Contact-dependent signalling.

Question 3

Main function of signal transduction pathways?

Answer 3

Amplify response

Question 4

How is the signal terminated in transduction pathways?

Answer 4

Hydrolytic enzymes, membrane transport

Question 5

Where is best to inhibit signal pathways?

Answer 5

Higher up the pathway is better as more specific; lower down are likely to infringe on other pathways that lead to the same element. Therefore drugs should target receptor itself ideally.

Question 6

Second messengers?

Answer 6

Small molecules synthesised in cells in response to an external signal, responsible for IC signal transduction i.e Ca2+ ions, DAG, cAMP, JAK.

Question 7

Four ways specificity of biosignalling can be influenced?

Answer 7

1. Molecular complementarity between signal and receptor
2. Cell-specific expression of receptors
3. Cell-specific expression of signal transduction proteins
4. Cell-specific expression of effector proteins (e.g. epinephrine response in liver/muscle/adipose.

Question 8

Direct ligand-gated channels?

Answer 8

When signal molecule binds, gate allows ions e.g. Na+ through channel.

Question 9

G-protein coupled receptors?

Answer 9

7 transmembrane domains. Ligands include odours, hormones, pheromones. Ligand binds to GCPR, conformational change allowing guanine exchange and activation of associated G protein (exchanges bound GDP for GTP).

Question 10

Which G protein subunit uncouples?

Answer 10

GPCR binds to G protein; releases GDP; GTP replaces it and alpha subunit dissocates from B and y; can then affect other signalling/effector proteins.

Question 11

9 processes that GPCR are involved in?

Answer 11

Vision, taste, smell, behavioural/mood regulation, homeostasis (e.g. water balance), inflammation, immune system regulation, ANS transmission, cell density sensing.

Question 12

V2R physiology?

Answer 12

GPCR on collecting ducts; AVP binds to it and stimulates water resorption. Inactivating V2R mutations (X c’some) causes congenital nephrogenic diabetes insipidus in males (cannot concentrate urine). Gain of function causes ‘SIADH’-like picture with undetectable AVP (NSIAD) where urine is highly concentrated and serum is hyponatraemic.

Question 13

What receptor type is EGFR?

Answer 13

Tyrosine-kinase linked.

Question 14

Effects of EGFR activation?

Answer 14

DNA synthesis, cell growth, survival. Frequently over expressed in human tumours.

Question 15

Intracellular steroid/thyroid type receptors?

Answer 15

4th and final type; found in cytosol or nucleus; small/hydrophobic messengers can enter cell/nucleus and activate. Includes steroid and thyroid hormones. Activated complex can act as a transcription factor!!!

Question 16

JAK-STAT signal transduction?

Answer 16

STAT protein regulates growth/survival/differentiation. TFs for this protein are activated by JAK; dysregulation seen in tumours (leads to angiogenesis, enhanced survival, immunosuppression).

Question 17

VHL disease?

Answer 17

Type 1 = without phaeochromocytoma; T2 = with high risk of phaeo.

Question 18

What pathway is activated by EGFR and Her2/neu receptors?

Answer 18

Ras-Raf-MAP kinase; causes cell proliferation. Often get ligand-independent signalling in RAS mutations (in 30% of cancers) causing constitutive activation of MAP kinase.

Question 19

How may cancer cells acquire sustained proliferative capacity?

Answer 19

1. Overproduction of GF ligands
2. Overproduction of GF receptors
3. Production of structurally altered receptors (can do ligand-independent signalling)
4. Activation of IC pathway components so that becomes ligand-independent.

Question 20

Which are the prototypical tumour suppressors?

Answer 20

Rb and TP53; act as central control elements (can halt cell cycle or causes death). Cancer cells can break free of these inhibitory signals.

Question 21

A growth-inhibitory protein commonly mutated in tumours?

Answer 21

Rb (loss of restraint in G1-S transition).

Question 22

How do random mutations lead to carcinogenesis?

Answer 22

Occasionally mutations confer selective advantage, allowing dominance in local environment. Get successful clonal expansions of premalignant cells, each expansion triggered by random enabling mutation. Accelerate process by compromising surveillance and repair systems.

Question 23

Most important regulator of apoptosis?

Answer 23

TP53. Can induce apoptosis in response to genomic damage. Commonly lost in cancer cells.

Question 24

Autophagy?

Answer 24

Catabolic processes where cell constituents are are degraded but cell survives (in response to stress [namely nutrient starvation]). Usually happens at low levels. Metabolites are recycled for biosynthesis.

Question 25

Autophagy in cancer cells?

Answer 25

Happens at high rates due to nutrient starvation (allows recycling for biosynthesis). Also 2ndary to chemo/radio (induce elevated autophagy levels; actually cytoprotective (reversible dormancy achieved) allowing survival of potent anticancer agents.

Question 26

Necrosis in cancer cells?

Answer 26

Necrosis causes immune cells recruitment; process is tumour promoting as increase angiogenesis/proliferation/invasion. Necrotis is cancer cells may paradoxically promote carcinogenesis.

Question 27

What do normal cells do once become confluent/deprived of serum/GFs?

Answer 27

Enter quiescent G0 state (stop proliferating)

Question 28

What is the purpose of G2?

Answer 28

Allows repair of any errors in DNA synthesis (S) before mitosis (M)

Question 29

What do products of TS genes do?

Answer 29

Bind and deactivate cyclin-CDK complexes, halting cell cycle.

Question 30

Characteristic change in cell cycle in malignancy?

Answer 30

No pause in G1/S so damaged DNA is duplicated, meaning accumulate changes that may confer proliferative advantage.