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Cancer & Genetics > Cell Proliferation > Flashcards

Cell Proliferation Flashcards

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Biology 101 flashcards
1
Q

What is cell proliferation?

A

-Inc. cell numbers
-Growth must occur
–> tissue homeostasis (apoptosis & proliferation balance)

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2
Q

What does deregulation of apoptosis & cell proliferation cause?

A

-Cancer
-Neurodegenertion

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3
Q

What signals to cells to divide & proliferate?

A

Mitogens

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4
Q

What are mitogens?

A

-Growth factors
-Cytokines

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5
Q

Role of mitogens?

A

To signal to cells to begin to divide and proliferate, by signalling for proteins to be made which allows the R-point to be overcome.

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6
Q

Where are mitogens used in the cell cycle?

A

G1 = mitogen dependent (to get past R-point = restriction point)

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7
Q

What do mitogens signal to?

A

Cell membrane bound receptors - e.g., receptor tyrosine kinase family

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8
Q

Why is dimerisation of RTKs important?

A

-Signal specificity
-Signal activity (i.e., what is causes in the downstream functions)
-Redundancy (if something goes wrong in one rec still have other to rely on)

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9
Q

What is the ErbB receptors tyrosine kinase family?

A
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10
Q

Which erbB has no kinase domain?

A

erbB3/HER3

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11
Q

What ligands are for erbB2/HER2?

A

No specific ones

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12
Q

What ligands are for erbB3/HER3?

A

Heregulins

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13
Q

What ligands are for erbB4/HER4?

A

NRG2, NRG3, Heregulins

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14
Q

Role of EGF (ligand - growth factor)?
ERK pathway

A

Is a POG - so activates cell proliferation

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15
Q

How is ERK pathway regulated (involving EGF ligand) so not = OG?

A

-Prevent EGF release (target metalloproteinases = involved in exocytosis & cleaving off of EGF - as is a protein made intracellularly)
-Inactivate EGFR
>Internalise (endocytosis & send to
lysosomes to destroy)
-Cells will die if signalling = excessive (induce apoptosis)

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16
Q

How can cancers occur in EGFR signalling pathways (x5)?

A

-Deregulate endosome - so no endo of EGFR
-over activate metalloproteinases = more exo of EGF
=> more EGF

-Overexpress EGFR = more signalling
-Mutation in kinase domain = always active/phosphorylating (even if nothing bound)
-Deletion (truncating) of ligand binding domain = shorter so ligand not have to bind

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17
Q

What are 3 types of therapeutics to target EGFR to prevent cancer?

A

1 - Inhibitors = stop EGF binding
2 - Prevent autophosphorylation = tyrosine kinase inhibitors
3 - No het/hom dimers - so none of +ves of dimerisation

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18
Q

How might cancers to EGFRs be resistant to inhibitors?

A

-T790M mutation = means that the drug will not bind to the active site of the RTK (rec) - so can’t regulate/stop cell prolif
-EGFR T790M amp = means genome will code for EGFRs with mutated active site which inhibitor drugs cannot bind to
-HER2 amp = if have inhibition of HER1/EGFR (due to drugs) = cancers will become reliant on other GF recs
-B-RAF mutations = bypassing some of pathway (skip to downstream signalling) - start at Ras. - Mutated Ras always bound to GTP (always active) - mutation to Raf = v. active kinase - so more rapid ERK signalling

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19
Q

What are cyclins?

A

Proteins that regulate the cell cycle

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20
Q

What cyclin is involved in early G1?

A

Cyclin D

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21
Q

What cyclin is involved in late G1?

A

Cyclin E

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22
Q

What cyclin is involved in S?

A

Cyclin A

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23
Q

What cyclin is involved in early G2?

A

Cyclin A

24
Q

What cyclin is involved in late G2?

A

Cyclin B

25
Q

What cyclin is involved in mitosis (M)?

A

Cyclin B

26
Q

What is common/the same in all cyclins?

A

A domain - chain of AAs which is found in all cyclins (have a cyclin box)

27
Q

What are Cyclin Dependent Kinases (CDKs)?

A

Cyclins which depend on kinases (cyclins regulate CDKs)

28
Q

What CDKs binds to cyclin D in early G1?

A

CDK4
CDK6

29
Q

What CDK binds to cyclin E in late G1?

A

CDK2

30
Q

What CDK binds to cyclin A in S?

A

CDK2

31
Q

What CDK binds to cyclin A in early G2?

A

CDK1

32
Q

What CDK binds to cyclin B in late G2

A

CDK1

33
Q

What CDK binds to cyclin B in mitosis?

A

CDK1

34
Q

Purpose of cyclins binding to CDKs?

A

Leads to activation of the kinase function in the CDKs

35
Q

What happens when cyclins bind to CDKs (in order to activate K in CDK)?

A
  • Inactive = T-loop blocks active site - ATP can’t bind
    -Active = cyclin causes confirmational shape change to T-loop = PARTIALLY ACTIVE
36
Q

How are CDKs made fully activated?

A

CDK-activating kinase = phosphorylates T-loop = so ATP can bind

37
Q

How are CDKs inactivated?

A

Wee1 kinase = carries out inhibitory phosphorylation (+ another Pi) = inactive as cyclins & ATP can’t bind as well

38
Q

How would CDKs inactivated by Wee1 be reactivated?

A

Cdc25 phosphatase = carries out activating phosphorylation (normal type + Pi)

–> remove inhibitory phosphate from tyrosine & threonine residues

39
Q

How does a cell go from G1 to S?

A

-Rb normally in complex w/ E2F1 (a TF) (Rb is not very phosphorylated - hypo Rb)
-E2F1 = inactive when bound to Rb (can’t bind to promoters)
-CDK4/6/cyclin D = phosphorylates Rb (inactivates Rb partially)
***
-CDK2/cyclin E = phosphorylates Rb (so Rb = hyperphosphorylated)
-E2F1 can’t complex w/ Rb (Rb = fully inactivated) - binds to promoters of genes for S phase proteins

40
Q

What happens in-between CDK4/6/cyclin D hypophosphorylating Rb and CDK2/cyclin E hyperphosphorylating Rb? (***)

A

-Cyclin E must be produced!
–> so the phosphorylation of Rb by CDK4/6/cyclin D = partially inactivates Rb
-So some E2F1 = active
-E2F1 (small amount - not ON/OFF switch) binds to promoters of gene to transcribe cyclin E (for late G1)

41
Q

What happens after Rb has been fully inactivated from CDK2/cyclin E phosphorylation?

A

E2F1 binds to promotors of gene to transcribe cyclin A (for S phase) –> this pushes past R-point

42
Q

How do Rb mutations cause cancer?

A

Stops Rb from ever binding to E2F1 - so E2F1 can move around binding to promoters of specific genes constantly stimulating S phase being entered (cell prolif)

43
Q

What is 1st needed for DNA replication to begin?

A

Pre-replication complex of proteins must bind to DNA near where DNA pol. binds = CDC6, ORC, CDT1

44
Q

Role of CDK2/cyclin A complex in S?

A

Phosphorylates helicase (enz) - so Helicase can unwrap DNA

45
Q

How do we ensure DNA is only replicated once?

A

Pre-replication factors:
-CDC6 = moved out nucleus
-CDT1 = degraded

46
Q

Role of CDK1/cyclin A in early G2?

A

To phosphorylate CDC25 (an activating phosphatase)

47
Q

What happens to CDC25 once is phosphorylated by CDK1/cyclin A in early G2?

A

Carries out activating phosphorylation on the previously inactive CDK1/cyclin B complex = removes an inhibitory Pi bound to CDK1 here

48
Q

How is CDK1/cyclin B inactivated again - when not needed so does not enter late G2 constantly?

A

Wee1 kinase (an inhibitor) = adds an inhibitory Pi to CDK1/cyclin B = inactive form
(= +ve feedback process)

49
Q

Role of CDK1/cyclin B in mitosis (x3)?

A

-Phosphorylates condensin (protein) = supercoils sister chromatids so are ready to separate & segregate (DNA compacts - fold/coil)
-Phosphorylates proteins of nuc env - so disassembles
-Activates centrosomes so move apart * increase microtubule length (grow)

50
Q

What stimuli can activate checkpoints?

A

-Errors in DNA rep - DNA pol
-Chrom dereg - how pack up
-Excess mit signal - lack GFs & nutrients

51
Q

Role of CDK inhibitor proteins?

A

To stop specific CDKs so don’t allow cell cycle to progress when an error e.g., DNA damage is detected

52
Q

Types of CDK inhibitor proteins?

A

-INK4A family = p16INK4A, p14ARF
-CIP/WIP family = p27KIP1, p21CIP1

53
Q

What are some types of POGs (x4) & TSGs (x6) involved in cell cycle?

A

-Wee1 = TSG - as inhibits CDK by inhibitory phosphorylation
-CDC25 = POG = removes inhibitory phosphorylation

54
Q

What are the activators of single and double strand DNA breakage (DNA damage example)?

A

-Single = ATR
-Double = ATM
–> BOTH = protein kinases (so will phosphorylate something)

55
Q

How is single strand breakage regulated?

A

-ATR phosphorylates residue S345 on CHK1 (protein)
-Auto-phos to S296 residue of ATR
-Wee1 = activated - so can inhibit CDK (add inhibitory Pi)
-CDC25A = inhibited via degrading - so can’t remove inhibitory Pi from CDK

56
Q

How is double strand breakage regulated?

A

-ATM phosphorylates CHK2 (protein)
-CDC25C = inhibited - move into cytoplasm so can’t inhibit CDK - not in nucleus

Cancer & Genetics (4 decks)

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