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Year 2 - Cancer > Cancer 4 > Flashcards

Cancer 4 Flashcards

1
Q

what phase are cells in if they are not dividing?

A
  • they will be in G0
  • quiescent phase
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2
Q

what is Mcy and what is its role?

A
  • Mcy is a transcription factor (protein that controls the expression of other genes)
  • the concentration of Myc is very low when the cell is in

the quiescent G0 phase

  • when cell division is triggered by adding a growth factor there is a rapid and dramatic rise in Myc
  • This correlates with cells moving out of G0 and into G1
  • Myc controls many genes in the cell cycle
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3
Q

What are the three key components of signaling pathways?

A
  • regulation of enzyme activity by protein phosphorylation (kinases)
  • the role of the adapter proteins
  • regulation by GTP - binding proteins
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4
Q

how are growth factors stimulated by signaling pathways?

A
  • The growth factor arrives and it binds to a receptor (normally tyrosine kinase type receptors)
  • it then acts via a small GTP binding protein (Ras)
  • this then triggers a kinase cascade (very fast)
  • this then triggers the activation of genes that are required for the progression of cells through the cell cycle (slower - 1 hour)
  • one of the genes triggered early in the kinase cascade is c - Myc which goes on to regulate the expression of many other genes

*

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5
Q

explain signaling by peptide growth factors?

A
  • the phosphorylated receptor protein tyrosine kinase recruits adapter and signaling proteins
  • the receptors normally sit on the plasma membrane as monomers but most growth factors are dimetric
  • the dimetric growth factor binds to x2 tyrosine kinase and brings them close
  • when the receptors are close the tyrosine kinase cross - phosphorylates with the partner receptor
  • Tyrosine kinases use the gamma phosphate of ATP to phosphorylate tyrosine residues in proteins
  • The phosphorylated domains on the tyrosine kinase receptors act as docking sites for adaptor proteins
  • The adaptor proteins contribute to downstream signalling
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6
Q

give an example of interfering with growth factor signalling?

A
  • there is an antibody called Herceptin that inhibits the her2 receptor tyrosine kinase
  • this is important in blocking the early stages of growth stimulation
  • that can be used in tumors eg. breast cancer
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7
Q

give an example of an important adaptor molecule?

A

Grb2

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8
Q

what do adaptor proteins bind to?

what is the structure of an adapter protein?

A
  • the adapter proteins bind on to the phosphorylated tyrosines which act as docking sites
  • adaptor proteins are often modular
  • they are made up of domains that are mixed and matched
  • These different domains are important in molecular recognition
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9
Q

do adapter proteins have enzymic function?

A
  • The adaptor molecules have no enzymatic function = they don’t do anything other than bringing other proteins together
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10
Q

what are the 3 types of protein-protein interactions of Grb2?

A
  • SH2 = binds to the phosphorylated tyrosines of the receptor

binds to RPTK

  • SH3 (there are two copies) = bind to the proline-rich regions of other proteins

binds to Sos

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11
Q
  • Grb is bound to the RPTK via its SH2 domain and it binds to a protein called Sos through its SH3 domains
  • Sos is an exchange factor for Ras
  • Grb2 is always bound to Sos
  • when RPTK is activated there is phosphorylation of the receptor
  • Then Grb2 (with Sos attached) binds to these phosphorylated tyrosine domains
  • Sos then is close enough to activate Ras
  • Sos allows the exchange of `GDP for GTP in ras to form a GTP bound form of Ras
  • this changes the conformation of Ras which puts it in an active state that is able to signal and allow the propagation of the signal
  • it is important that the Ras protein binds with the plasma membrane
A
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12
Q

why might interfering with the membrane binding of Ras be helpful?

A
  • can make a good anti-cancer therapy
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13
Q

what turns Ras off and on?

A

Ras is on when it is GTP bound

Ras is off when it is GDP bound

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14
Q

what catalyses the replacement of GDP with GTP?

A

sos

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15
Q

how does Ras turn itself on and off?

A
  • This is a self-regulating system so Ras can turn itself off
  • the GTP binding protein is able to hydrolyze GTP to GDP to turn itself off = ( intrinsic GTP hydrolysis capability )
  • but it is very slow
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16
Q

what external proteins turn ras on?

what external proteins turn ras off?

A
  • Exchange factors (e.g. Sos) that turn it ON
  • GTPase activating proteins (GAPs) that turn it OFF
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17
Q

what is the main function of ras?

why is it important that it is carefully controlled?

A
  • it is very important in growth factor stimulatory pathways
  • it is important that ras is switched off in order to prevent uncontrolled division
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18
Q

what might happen to Ras in cancer?

A
  • in cancer the ras protein is mutated in ways that cause the Ras protein to constantly be in the GTP bound form
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19
Q

show how RPTKs signal to Ras?

A
  • there are dimeric activated receptors
  • adaptor protein Grb2
  • Grb2 binds to phosphorylated tyrosine
  • this binds tightly to the exchange factor sos (activating protein)
  • sos then mediates the action of Ras at the membrane
  • allowing ras to transmit signal downstream
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20
Q

give 2 example of point mutations in cancer affecting ras?

A
  • V12Ras
  • L61Ras
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21
Q

explain the V12Ras mutation:

A
  • the glycine in position 12 of Ras is changed to valine due to a point mutation
  • the side chain changes from hydrogen to a hydrophobic side chain
  • this prevents GAPs from binding to Ras
  • this means Ras cannot be turned off very easily
22
Q

explain the L61Ras mutation:

A
  • glutamine in position 61 is converted to leucine
  • this is a single base change in the genome
  • the side chain switches from being an amide to being a hydrophobic side chain
  • This mutation inhibits the intrinsic GTPase activity of the Ras protein
  • Ras is then constantly on and always giving growth stimulatory signals
23
Q

how does Ras activate the protein kinase cascade?

A
  • GTP bound Ras binds to a kinase and then that kinase activates other kinases
  • there is a chain of kinase phosphorylation
  • The kinase cascade that is specifically involved in the growth stimulatory signaling is called the ERK cascade
  • ERK cascades belong to the family of MAPK cascades

ERK cascade (extracellular signal regulated kinase cascade)

MAPK cascades (mitogen activated protein kinase cascade)

24
Q

what kinases make up the ERK kinase?

A
25
Q

what is the end result of the ERK cascade?

A
  • at the end of the cascade, the last kinase phosphorylates a number of proteins and changes their activity
  • among the proteins being phosphorylated there are gene regulatory proteins (transcription factors)
  • once phosphorylated the transcription factors go on to regulate gene expression
  • the most important gene to be turned on by the ERK pathway is c- Myc gene
  • Myc and Ras are key molecules in stimulating growth
  • Myc and Ras are oncogenes
26
Q

what are Cyclin-dependent kinases?

have are they controlled?

A
  • These are serine-threonine kinases
  • when they bind to an activating protein called cyclin they are activated
  • The Cdks are ALSO controlled by phosphorylation
27
Q

what is the role of cyclins?

A
  • cdks are activated by binding to cyclins
  • Cyclins are transiently expressed during the cell cycle
  • once they have activated the Cdks the cyclins are degraded
28
Q

when is cyclin necessary within the cell cycle?

A

At the start of mitosis

  • the M phase promoting factor controls mitosis
  • there is a release of mitotic cyclin which activates the Cdk
  • once the Cdk has completed its role it is degraded and the Cdk is chopped up

Just before DNA replication

  • At the start of DNA replication, there is a Cdk that is turned on by binding to an S phase cyclin
  • again once the Cdk has carried out its function it is degraded
29
Q

what does the mitosis promoting factor consist of?

A
  • cdk1
  • mitotic cyclin (cyclin B)
30
Q

show on a graph what the pattern of cyclin release is?

A
  • cyclical nature
  • it shows that cyclins are expressed during mitosis and then they are degraded and this happens in a cyclical nature
31
Q

how are cdks regulated by phosphorylation?

A
  • Cdk1 binds to cyclin B
  • the Cdk- cyclin complex is usually inactive on its own
  • the complex undergoes 2 phosphorylation reactions that regulate Cdk activity
  • Cdk has to be activated at specific sites to become activated
  • This activation is performed by Cdk activating kinase (CAK)
  • Balancing this is an inhibitory kinase called Wee1
  • Even though Cdk1 is bound to cyclin, it needs the inhibitory phosphate to be taken off before it can function
  • Cdc25 takes off the inhibitory phosphate that was put on by Wee1
  • only then is the MPF active
32
Q

how does dephosphorylation activate Cdk1?

A
  • Dephosphorylation of the inhibitory site of Cdk1 by Cdc25 activates it towards the end of interphase
  • Active MPF is able to phosphorylate Cdc25 to increase its activity
  • Cdc25 takes off more inhibitory phosphate
  • this is a form of positive feedback that drives mitosis
33
Q

how do cyclins and Cdk 1 help with mitosis checkpoints?

A
  • whilst MPF is active at the end of metaphase it phosphorylates a number of key substrates that are involved in the mitotic process
  • this puts mitosis on hold
  • mitosis cannot progress to anaphase until the signal has been released
  • Once the kinetochores are correctly attached to the microtubule spindles at the end of metaphase
  • a signal is released that causes cyclin B to be degraded
  • When cyclin B is degraded, Cdk1 becomes inactive
  • this means that the substrates (which were keeping mitosis on hold) are dephosphorylated so then mitosis can progress
34
Q

what cyclins and cdks are needed at different stages of mitosis?

A
  • different cyclins and cdks control different stages of mitosis
  • the same cdk is being used but for different purposes
  • this is because when cyclin binds to Cdk it actually changes its substrate specificity
  • It also changes substrate accessibility
  • this feature allows you to use the same Cdk in different stages of the cell cycle
35
Q

how does growth factor stimulation promote the transition of G1 to G2?

A
  • growth factors come and bind to the receptor protein tyrosine kinase
  • through Ras this triggers a kinase cascade
  • this leads to phosphorylation of transcription factors that turns on the expression of c-Myc
  • Myc is a transcription factor and one of its jobs is to stimulate the transcription of cyclin D
36
Q

how does Myc result in the synthesis of cyclin E?

A
  • Myc is a transcription factor that stimulates the transcription of cyclin D
  • Cyclin D activates Cdk4 and Cdk6 to stimulate the synthesis of cyclin E
  • this triggers the cell cycle
37
Q

how do cyclins and cdks give timing and direction to the cell cycle?

A
  • production of Myc leads to the synthesis of cyclin D
  • cyclin D leads to production of active Cdk4/6 / cyclin D complex
  • This Cdk- cyclin complex then stimulates the synthesis of the next cyclin
  • each cyclin is involved in stimulating the synthesis of the next cyclin
  • this gives the cell cycle both timing and direction
38
Q

what is the function of nuclear lamins?

A
  • nuclear lamins cause the breakdown of the nuclear envelope
  • Breakdown of the nuclear envelope is caused by phosphorylation of the nuclear lamins
39
Q

what does start kinase do?

A
  • start kinase is a complex of cdk2 and cyclin E
  • it phosphorylates substrates needed for G1
  • one of the most important proteins that is phosphorylated by start kinase is retinoblastoma
40
Q

explain how retinoblastoma regulates the cell cycle?

A
  • Retinoblastoma is a key protein in regulating the cell cycle
  • In the resting G0 state, retinoblastoma is unphosphorylated and active
  • at G0 it is bound to a family of transcription factors called E2F
  • whilst the retinoblastoma is bound to E2F everything is turned off
  • Retinoblastoma is a target for Cdk4/6 cyclin D kinase (which becomes active following Myc induction)
  • as the protein becomes phosphorylated, it becomes inactive and loses its affinity for E2F so it releases E2F
  • E2F transcription factors can then bind to promoters in the nucleus of genes that are involved in cell cycle progression eg. cyclin E
  • Retinoblastoma acts as a brake in the cell cycle, when it is unphosphorylated it prevents the movement of the cell cycle
  • it is a TUMUOR SUPPRESSOR GENE
  • Many tumours have reduced levels of retinoblastoma

so it can’t regulate the E2F activity

41
Q

what other genes are regulated by E2F?

A
  • E2F transcription factors regulate proto=oncogenes eg. Myc
  • They also control genes that are involved in the S phase eg. thymidine kinase
  • Cyclin E is one of the first targets of E2F transcription factors
  • it begins the transcription of cyclin E to bring on the next phase of the cell cycle
42
Q

what happens after the inital release of E2F?

A
  • The initial release of E2F after phosphorylation will allow the transcription of cyclin E
  • Cyclin E will then form a complex with Cdk2
  • Retinoblastoma is also a target for phosphorylation by the active Cdk2 - cyclin E complex
  • This means that retinoblastoma becomes further phosphorylated and it releases more E2F
  • so the concentration of E2F is increased
43
Q

overview of Cdk activity?

A
  • Myc turns on cyclin D, which complexes with Cdk4/6
  • This Cdk4/6=cyclin D complex phosphorylates retinoblastoma
  • this allows E2F to start being released in the cytoplasm and stimulates cyclin E
  • Cyclin E forms a complex with Cdk2 and this complex further phosphorylates retinoblastoma leading to increase in E2F
  • The increase in E2F concentration means that it can now bind to targets with lower affinity
  • The cyclin A gene promoter is not activated until the E2F concentration is high enough
  • cycle continues
44
Q

how are CDKs inhibitors?

A
  • there are 2 families of inhibitors called Cdk inhibitors that add another level of regulation
    • INK4 family
    • CIP/KIP family
45
Q

what does the INK4 family do?

A
  • INK4 family is active in G1
  • they inhibit Cdk4/6 by displacing cyclin D
46
Q

what does the CIP/KIP family do?

A
  • active in S phase and inhibits the Cdk/cyclin complexes by binding to it
47
Q

what must happen to the inhibitors for the cell cycle to progress?

A
  • For the cell cycle to progress these inhibitors need to be degraded
  • The degradation of the Cdk inhibitors have been superimposed
48
Q

what is the importance of cell cycle regulators in cancer?

A
  • Genes that are commonly lost in cancers are tumour suppressor genes
  • Genes that are commonly over=expressed/over=produced in cancers are oncogenes
49
Q

what are oncogenes?

A
  • derived from normal protooncogenes that become mutated
  • Many cell surface tyrosine kinase receptors are oncogenes
  • when they are overexpressed they cause excessive growth
50
Q
A
51
Q

what happens to tumour supressors in cancer?

A
  • they become inactivated

Year 2 - Cancer (15 decks)

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