GI Dysfunction Flashcards

1
Q

What is p53?

A

A transcription factor
Regulates G1/S checkpoint by preventing progression into S phase when the environment is not favourable
Tumour suppressor gene

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2
Q

What happens to p53 when the environment is favourable for cell proliferation?

A

p53 is ubiquitylated by mdm2 and undergoes proteasomal degradation

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3
Q

What happens to p53 when the environment is NOT favourable for cell proliferation?

A

DNA damage causes p53 phosphorylation to protect it from ubiquitylation
p53 transcribes genes including p21
p21 inhibits CDK4 and CDK6

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4
Q

What does Retinoblastoma do under normal conditions?

A

Binds to/Inhibits the E2F transcription factor

Prevents transcription of E2F controlled genes that are required for cell cycle progression into S phase

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5
Q

What are cyclins and what do they do?

A

Cyclins are proteins that regulate the cell cycle
Different cyclins are present at different times during the cell cycle
Needed to activate cyclin dependent kinases

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6
Q

What are CDKs?

A

Cyclin dependent kinases

Phosphorylate targets within cell, allowing progression past a checkpoint

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7
Q

How is Retinoblastoma inhibited?

A

It becomes phosphorylated by CDK4 and CDK6

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8
Q

What is glycogenolysis?

A

Glycogen breaks down to form glycogen and glucose-6-phosphate
Sequential removal of monomers
Catalysed by glycogen phosphorylase

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9
Q

What is the name of the reaction taking place during glyogenolysis?

A

Phosphorolysis

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10
Q

How is glucose used to generate ATP?

A

Glucose undergoes glycolysis to produce pyruvate
Pryruvate enters the citric acid cycle in a mitochondria
Reduced products undergo oxidative phosphorylation in the electron transport chain

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11
Q

Where does glycogenolysis takes place?

A

Muscle cells and liver cells

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12
Q

What is gluconeogenesis?

A

Glucose is created from sources other than glycogen e.g. glycerol and amino acids

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13
Q

What is insulin?

A

Peptide hormone release by beta cells of the pancreas in response to high blood glucose

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14
Q

What downstream effects does insulin have?

A

Upregulates insertion of GLUT4 transporter into the membrane of adipose and muscle cells (and liver???)
WHAT ELSE

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15
Q

What is glucagon?

A

Peptide hormone released by alpha cells of the pancreas in response to low blood sugar

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16
Q

What downstream effects does glucagon have?

A

Upregulates glycogenolysis

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17
Q

What do GLUT transporters do?

A

Facilitates transport of glucose across cell membranes using the glucose concentration gradient, via conformational change

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18
Q

How many types of GLUT transporters are there?

A

14

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19
Q

What are the main GLUT transporters and where are they found?

A

GLUT 1 and GLUT 3 - most cells
GLUT 2 - liver and pancreas
GLUT 4 - adipose cells, skeletal and cardiac muscle

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20
Q

Where does absorption of nutrients take place?

A

Small intestine: duodenum (90%), jejenum and ileum

Large intestine: water and >10% nutrients

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21
Q

How are the different nutrients absorbed?

A

Carbohydrates (glucose, fructose, galactose) and amino acids are absorbed by cotransportation with sodium
Fats are absorbed with passive diffusion as they are lipophilic
All vitamines absorbed by passive diffusion

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22
Q

What are the possible ligands of the insulin receptor?

A

Insulin, IGF-1, IGF-2

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23
Q

What two signalling pathways are initiated by the insulin receptor?

A

MAPK cascade and PI3K

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24
Q

What two signalling pathways are initiated by the insulin receptor?

A

MAPK cascade and PI3K

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25
Q

Describe the MAPK cascade

A
  1. Ligand binds to insulin receptor
  2. Dimerisation and trans-autophosphorylation
  3. Attracts SH2 domain on Grb2
  4. Grb2 brings SOS
  5. SOS converts GDP on Ras to GTP
  6. Ras activates Raf
  7. Raf phosphorylates MEK
  8. MEK phosphorylates ERK
  9. ERK translocates to the nucleus to transcribe genes
26
Q

What happens in each stage of the cell cycle?

A
G0 - cell cycle arrest
G1 - Replication of everything except DNA
S - DNA replication
G2 - Preparation for division
M - mitosis
27
Q

What is checked at each cell cycle checkpoint?

A

G1/S - Is the environment favourable?

G1/M - Is all DNA replicated? Are all DNA errors corrected?

28
Q

What is a mitogen?

A

Substance that stimulate cell proliferation e.g. Insulin, EGF, VEGF, TGF-a

29
Q

Which checkpoint is mitogen dependent?

A

G1/S

30
Q

What is retinoblastoma?

A

Tumour suppressor protein

31
Q

What is APC (disease)?

A

Adenomatous Polyposis Coli

Form of colorectal cancer

32
Q

What is the cause of APC?

A

A mutation in the APC gene
No functioning destruction complex
No destruction of beta catenin
Uncontrolled cell proliferation

33
Q

What is beta catenin?

A

Transcription factor

Involved in the Wnt signalling pathway

34
Q

Describe the Wnt signalling pathway

A

Wnt binds to it’s receptor, Frizzled
This activates the intracellular Dishevelled protein
Dishevelled inhibits the GSK kinase in the beta-catenin destruction complex
No destruction
Beta catenin transcribes genes
Cell proliferation

35
Q

What is APC (protein) and what does it do?

A

APC is a protein in the beta-catenin destruction complex
Forms complex with a GSK kinase and actin
Phosphorylates beta-catenin, marking it for ubiquitylation and proteasomal degredation

36
Q

What is DCC?

A

The ‘deleted in colorectal cancer’ gene
Codes for a receptor present on the villi in the small intestine
Acts as a tumour suppressor gene AND oncogene, depending on whether the ligand is bound or not

37
Q

What is the function of DCC when the ligand is bound?

A

Netrin-1 binds
DCC stimulates MAPK cascade
Results in cell proliferation

38
Q

What is the function of DCC when the ligand is not bound?

A

No Netrin-1 bound

DCC stimulates apoptosis of the cell

39
Q

What is the cause of DCC?

A

A mutation in the gene for DCC
No functioning receptor to stimulate apoptosis
No suppression of growth

40
Q

How does DCC result in formation of villi?

A

Netrin-1 is present at the base of the villi, stimulating cell proliferation
Netrin-1 is absent at the tip of the villi, so DCC stimulate apoptosis here

41
Q

Symptoms of diabetes

A

Polyuria
Increased thirst
Increased hunger
Changes in vision as glucose is absorbed by the lens of the eye

42
Q

What is the cause of Type 1 diabetes?

A

Autoimmune destruction of beta pancreatic cells that produce insulin
Insulin-dependent

43
Q

What is the cause of Type 2 diabetes?

A

Cells become resistant to insulin, and less insulin is produced
Linked to obesity and lack of exercise

44
Q

2 possible treatments for diabetes

A

Insulin injections

Metformin - suppresses gluconeogenesis, to decrease glucose production

45
Q

What is recombinant DNA?

A

DNA that has been made by putting DNA from multiple different organisms together

46
Q

What are biologics?

A

Drugs that have been manufactured from living systems

Includes recombinant DNA and monoclonal antibodies

47
Q

What are monoclonal antibodies?

A

Antibodies generated by injecting an organism with the target antigen, so their adaptive immune system creates antibodies

48
Q

Uses of monoclonal antibodies

A
  1. Bind to and block receptors involved in cell proliferation e.g. HER2
  2. Bind to and block IL-2 receptors on T cells to prevent activation, to suppress the immune system. Useful for preventing organ rejection following transplant
  3. Antibody can be conjugated to a radioactive molecule and targeted to cancer cells, to kill the cells
49
Q

How are monoclonal antibodies made?

A
  1. Inject organism with target antigen via intraperitoneal injection
  2. Organisms spleen cells produce antibodies
  3. Extract spleen cells and fuse them with myeloma cells to create hybridomas
  4. Hybridomas produce monoclonal antibodies
50
Q

How can you test if an organism is producing antibodies?

A

Use a test bleed to test if antibodies have been produced

51
Q

How do you screen hybridomas to check that they have fused correctly?

A

Grow them on HAT medium

Non fused spleen/myeloma cells die

52
Q

What are first generation monoclonal antibodies?

A

Antibodies that have been extracted from a non-genetically modified organism

53
Q

What are second generation monoclonal antibodies?

A

The organism has been genetically modified before injecting with antigen
This enables creation of chimeric or humanised mAbs

54
Q

What are chimeric mAbs?

A

The Fc region of the antibody is human but the Fab region is not

55
Q

What are humanised mAbs?

A

Majority of the antibody is human

56
Q

How is recombinant DNA created?

A

Host plasmid cleaved using restriction enzymes
Creates sticky ends
Annealing of new gene (e.g. insulin gene) into plasmid
Forms recombinant plasmid

57
Q

Uses of recombinant DNA

A

Recombinant plasmid inserted into bacteria
Bacteria produces protein
Can be used to make insulin and glucagon

58
Q

What is the structure of an antibody?

A
2 long heavy chains
2 short light chains
Chains connected by disulfide bond
Fab region (antigen binding)
Fc region
59
Q

What is the difference between monoclonal and polyclonal antibodies?

A
Monoclonal = one species of antibody, produced by identical immune cells
Polyclonal = mixture of antibodies, produced by several types of plasma cells
60
Q

Pros/Cons of humanised antibodies

A

Pros: Less likely to cause immune reaction, Longer half life
Cons: Takes longer to develop, More expensive

61
Q

What is parenteral administration?

A

Any systemic form of administration that is not through the GI tract

62
Q

What is the two functions of IL-2?

A

Proliferation of T cells

Activates JAK/STAT receptors