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Y2 MCD Cancer > cell cycle > Flashcards

cell cycle Flashcards

cell cycle molecular control: explain the principle of molecular regulation of the cell cycle, including the role of cyclins and their kinases

1
Q

what does premature, aberrant mitosis result in

A

cell death

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2
Q

3 features of tumours which show relevance of appropriate cell division regulation

A

most solid tumours (with mutations in oncogenes and tumour suppressor genes) are aneuploid (abnormal chromosome number), various cancer cell lines show chromosome instability (+/- whole chromosomes), perturbation of protein levels of cell cycle regulators is present in different tumours

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3
Q

what stops cells from growing

A

contact inhibition (spatial limit), which is lost in tumours

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4
Q

what is one of the most successful anti-cancer strategies in clinical use

A

attacking machinery that regulates chromosome segregation

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5
Q

why do cells enter G0 and what happens in this phase

A

in absence of growth signals (not constantly dividing), become quiescent e.g. liver hepatocytes

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6
Q

what happens at the restriction point in G1

A

cell monitors its own size and external signals

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7
Q

what is c-Myc

A

ongogene overexpressed in many tumours

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8
Q

what does c-Myc do physiologically

A

acts as a transcription factor to stimulate expression of cell cycle genes (synthesised when growth factor present)

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9
Q

3 key components of signalling pathways

A

regulation of enzyme activity by protein phosphorylation (kinases), adapter proteins, regulation by GTP-binding proteins

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10
Q

growth factor stimulation of signalling pathway: membrane

A

mitogenic growth factor from other cells binds to EC part of receptor (master regulator)

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11
Q

growth factor stimulation of signalling pathway: cytosol

A

receptor protein tyrosine kinase -> small G (GTP-binding) protein (Ras) -> kinase binding

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12
Q

growth factor stimulation of signalling pathway: nucleus

A

immediate early genes (c-Jun, c-Fos, c-Myc - transcription factors) which control gene expression

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13
Q

how rapidly from when growth factor binds do early-response genes in nucleus become activated to activate cell cycle control system

A

15 minutes

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14
Q

how rapidly from when growth factor binds do delayed-response genes in nucleus become activated to activate cell cycle control system

A

> 1 hour

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15
Q

what does the receptor protein tyrosine kinase recruit

A

adaptor and signalling proteins

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16
Q

what 2 things are mutationally activated or overexpressed in many breast cancers

A

EGFR/HER2

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17
Q

in addition to activation, what is tyrosine phosphorylation providing

A

docking sites for adapter proteins (example of protein-protein interactions)

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18
Q

what can EC receptors be targeted with

A

anti-HER2 antibody in cancer therapy

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19
Q

example of tyrosine phosphorylation docking site protein and domains

A

Grb2 (domains: SH3 - SH2 - SH3)

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20
Q

adaptor proteins: define modular protein domains

A

functional and structural units that are copied in many proteins

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21
Q

adaptor proteins: function of some domains allowing molecular recognition

A

no enzymatic function of their own, but bring other proteins together

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22
Q

adaptor proteins: function of Grb2 SH3 domain

A

recognise proline-rich regions (constitutive) to bring in specific proteins with SH3 domains

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23
Q

adaptor proteins: function of Grb2 SH2 domain

A

bring in phosphorylated tyrosines (inducible, specific sequence domains)

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24
Q

what act as molecular switches

A

GTP-binding (G) proteins (not kinases)

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25
Q

example of an IC GTP-binding (G) protein

A

Ras

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26
Q

what activates Ras

A

when GTP binds: GDP dissociates, GTP binds and activates, causing Ras to bind to the plasma membrane to become activated

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27
Q

what provides exchange of GTP for GDP, activating Ras

A

exchange factors e.g. Sos, which bind to adaptor protein attached to phosphorylated tyrosine docking site

28
Q

how is Ras inactivated (95% in cell normally)

A

GTP hydrolysed by GTPAse activating proteins (GAP)

29
Q

receptor protein tyrosine kinase signal to Ras: what form is the binding growth factor, and effect on receptor

A

dimer, causing activation dimerisation of receptor

30
Q

receptor protein tyrosine kinase signal to Ras: how is the receptor activated

A

tyrosine kinase phosphorylated

31
Q

receptor protein tyrosine kinase signal to Ras: what adaptor protein activates the Ras-activating protein (exchange factor Sos)

A

Grb2 (consitutively i.e. Sos always bound to Ggrb2 via SH3 domains), which is bound to phosphorylated tyrosine on receptor

32
Q

effect of Ras being oncongenetically activated by mutations

A

increase amount of active GTP-loaded Ras

33
Q

2 methods by which a Ras mutation increases amount of active GTP-loaded Ras

A

V12Ras prevents GTPAse activating proteins binding (prevents inactivation), L61Ras prevents GTP hydrolysis

34
Q

what does Ras activate

A

protein kinase cascade

35
Q

specific Ras protein kinase cascade downstream

A

EC signal-regulated kinase (ERK) cascade (generically mitogen-activated protein kinase cascades)

36
Q

what is cell cycle control based on

A

cyclically activated protein kinases (Cdks)

37
Q

when are cyclin-dependent kinases (Ckds) present in proliferating cells

A

throughout cell cycle (not transient)

38
Q

what is cyclin-dependent kinase activity regulated by

A

interaction with cyclins, phosphorylation

39
Q

when are cyclins expressed

A

transiently at specific points of cell cycle (huge decrease at end of mitosis, before steadily climbing during interphase to peak in mitosis when M-phase-promoting factor (MPF) high, as cyclin forms MPF complex here)

40
Q

where are cyclins regulated, and fate of synthesised cyclin

A

regulated at level of expression, and synthesised then degraded

41
Q

effects of cyclin binding and activation of Cdks: G1 to S

A

binding of Cdk2 by G1 cyclin (e.g. cyclin E) forms start kinse (phosphorylates substrates at start), which triggers DNA replication memory (e.g. retinoblastoma protein which acts as a tumour suppressor)

42
Q

effects of cyclin binding and activation of Cdks: M

A

binding of Cdk1 by mitotic cyclin (e.g. cyclin B) forms M-phase-promoting factor (MPF which phosphorylates substrates at mitosis), which triggers mitosis machinery (e.g. nuclear laminins which cause breakdown of nuclear envelope)

43
Q

what amino acids does phosphorylation of proteins occur at by activated Cdks

A

serine or threonine, driving cell cycle progression

44
Q

when is retinoblastoma protein (pRb) inactivated

A

in many cancers

45
Q

what does activation of Cdks require, and why

A

3 stages: activating phosphorylation (Cdk-activating kinase (CAK)), removal of inactivating phosphorylation (inhibitory kinase), dephosphrylation at end of interphase (phosphatase Cdc25); complex so tight regulation for cell cycle

46
Q

during mitosis, what happens when Cdk1 and cycB are active

A

mitosis on hold, as key substrates phosphorylated (2 reactions)

47
Q

what causes cyclin B to be degraded in mitosis

A

signal from fully attached kinetochores

48
Q

3 effects of cyclin B degradation

A

Cdk1 inactivated, key substrates dephosphorylated, mitosis progresses

49
Q

what cyclin and Cdk is required during S phase

A

Cdk2, cyclin A

50
Q

2 effects of cyclins

A

activate Cdks, alter substrate specificity (substrate accessibility changes throughout cell cycle)

51
Q

stages of G0 to G1 transition

A

growth factor -> dimerisation and phosphorylation -> immediate early gene transcription factors (e.g. c-Myc) by Ras and ERK -> transcription of other genes (e.g. cyclin D) -> activation of Cdk4 and Cdk6 -> stimulate synthesis of cyclin E -> binds to Cdk2

52
Q

what gives direction and timing to cycle

A

Cdk sequential activation and stimulation of synthesis of genes required for next phase (c-Myc at G0 -> cyclin D/Cdk4/6 -> expression of cyclin E -> Cdk2-cyclin E -> expression of cyclin A -> Cdk2-cyclin A -> expression of cyclin B -> Cdk1-cyclin B)

53
Q

why is there cyclical activation of cyclins (appear transiently)

A

as cyclins are susceptible to degradation

54
Q

what acts as a brake on cell cycle

A

pRB (Rb - retinobastoma gene - is a tumour suppressor)

55
Q

how is pRb inactivated

A

progressively inactivated by Cdks phosphorylating at multiple sites

56
Q

regulation of gene expression by Rb (retinoblastoma gene)

A

activated found at G0, and binds to E2F transcription factor to inactivate it -> when phosphorylated by Cdks, releases E2F which transcribes genes e.g. cyclin E

57
Q

genes regulated by transcription factor E2F

A

many, including: oncogenes e.g. c-Myc; cell cycle e.g. cyclin A, E and pRb; DNA synthesis e.g. DNA polymerase

58
Q

multiple steps to synthesise correct cyclin

A

E2F activated and deactivated at different times by phosphorylation of Cdks, so each phosphorylation causes it to produce next cyclin

59
Q

what else regulates Cdks after cyclin binding to Cdk, and what must be done to allow cell cycle progression

A

Cdk inhibitors (CKIs), which bind to cyclin and Cdk; must be degraded to allow cell cycle progression

60
Q

2 families of CKI

A

INK4, CIP/KIP

61
Q

function of G1 phase CKIs (INK4)

A

inhibit Cdk4/6 by displacing cyclin D

62
Q

function of S phase CKIs (CIP/KIP)

A

inhibit all Cdks by binding to Cdk/cyclin complex

63
Q

when is degradation of G1 CKIs (INK4)

A

during G1

64
Q

when is degradation of S phase CKIs (CIP/KIP)

A

during S phase

65
Q

effect of tumours on CKIs, pRB, cyclins, c-Myc, Ras and Raf

A

loss of CKIs (inhibit) and pRBs (tumour suppressor), overproduction of cyclins (drive next stage; become oncogenes), c-Myc overexpressed, Ras and Raf mutationally activated

Y2 MCD Cancer (20 decks)

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