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Year 4 > Cancer > Flashcards

Cancer Flashcards

1
Q

Wnt signalling pathway

A

Wnt binds to LRP and Frizzled, this activates dishevelled which inhibits the destruction complex allowing B-catenin to accumulate. B-catenin can then translocate to the nucleus and displace co-repressors on TCF trascription factor. It recruits co-activators. and transcribes (cyclin D1 and c-myc which cause cell proliferation).

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2
Q

Ras signalling pathways

A

Growth factor binds to RTK causing phosphorylation of specific tyrosine residues. Grb2 binds to specific phosphotyrosine via SH2 domain and binds Sos1 via two SH3 domains. Sos1 is a GEF for Ras. Sos1 exchanges GDP for GTP on Ras. Ras then binds Raf causing it to dissociate from the plasma membrane. Raf is phosphorylated by MAPKKK to MEK, MEK is phosporylated by MAPKK to ERK (otherwise known as MAPK). ERK has nuclear and cytosolic substrates. In the nucleus is stabilises c-fos through direct phosphorylation allowing it to bind to c-jun forming transcriptionally active AP-1. AP-1 activity os required for cyclin D1 transcription for entry through r point in G1.

Ras-GTP can also acitvate PI3K p110 subunit cuasing it to be recruited independently of p85 activating the PKB/Akt pathway.

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3
Q

PKB/Akt pathway

A

Growth factor binds to RTK phosphorylating specific tyrosine residues. p85 regulatory subunit binds to specific tyrosine residue and recruits p110 catalytic subunit of PI3K. PI3K phosphorylates PIP2 in the plasma membrane to PIP3. PIP3 binds Akt causing conformational change exposing phosphorylation sites. PDK1 and PDK2 phosphorylate Akt activating it. Active Akt translocates to the nucleus and cytosol. Akt can activate the SCF complex causing degradation of p27 slowing down the cell cycle. Akt can also inhibit GSK3B which releases inhibition of cyclin D accelerating the cell cycle. (Akt activates mTOR promoting protein synthesis and inhibits FOXO preventing apoptosis)

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4
Q

TNF-a/NFkB pathway

A

TNF-a binds to TNF-a receptors causing them to trimerise. Trimer recruits adaptor protein TRADD which recruits RIP1 and TRAF2. This activates Ikk which phosphorylates IkB which is an NFkB repressor, therefore NFkB repression is lifted. IkB is degraded via the ubiquitin-proteasome pathway. This allows NFkB to translocate into the nucleus and bind to a co-activator causing it to transcribe target genes (e.g. promoting cell proliferation). (NFkB also regulates anti-apoptotic proteins such as TRAF. NFkB is often upregulated in cancer).

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5
Q

Notch pathway

A

Ligand binds to notch in EC domain cleaving it. This leads to a seconf cleavage of the IC domain. The IC piece is translocated to the nucleus. It binds to CSL transcription factor displacing repressors. The co-activator mastermind is recruited and the target genes are expressed. (roles in cell proliferation and angiogenesis).

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6
Q

Hedgehog pathway

A

(Hedgehog pathway usually switched off in adults) Patched normally inhibits smoothened. Hedgehog is secreted by tumour cells and binds to patched and results in the endocytosis of patched. As a result, the inhibition of smoothened is released and it moves from an IC vesicle to the plasma membrane in a cilium. Smoothened activates the Gli familiy of transcription proteins. Activated Gli proteins move to the nucleus and initiate the transcription of hedgehog target genes. Activated stromal cells then provide a favourable envirnment for the tumour. For example growth factors are expressed which promotes tumourigenesis or angiogenesis.

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7
Q

SAC

A

Mad1 is bound to kinetochores and recruits Mad2 changing its conformation from open inactive to closed active. Mad2 then binds to cdc20 preventing cdc20 activating APC/C (APC/C degrades securin which is a blocker for separase).
BubR1 acts as a pseudosubstrate binding to cdc20 and blocking substrate recruitment.

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8
Q

DNA damage cell cycle arrest pathway (ATM/ATR)

A

DNA damage is sensed by (broad spectrum of DNA damage) ATR and (double stranded breaks) ATM. ATR activates Chk1 which inhibits cdc25 and activates p53 which transcribes p21 which binds to CDK2-E inactivating it.
ATM activates Chk2 which activates p53 and inhibits cdc25 (same mechanism as above).
p21 stops CDK2-E from phosphorylating ORC of the pre-RC so DNA synthesis cannot begin.

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9
Q

G1-S transition control

A

Growth factor pathways like ras and raf transcribe cyclin D allowing the formation of CDK4/6-D. CDK4/6-D phosphorylates Rb (Rb along with HDAC are usually bound to E2F transcription factor repressing activity) and causes HDAC to dissociate. HAT can now bind to E2F and transcription of CDK2 and cyclin E occurs. The CDK2-E complex forms and this phosphorylates ORC of the pre-RC triggering DNA replication. CDK2-E also phosporylates cdc6 which causes the pre-RC to be degraded. This ensures there is only one replication of DNA per cell cycle.
p16 binds to CDK4/6 and prevents cyclin D from binding therefore preventing transition through R point.
p21/27 bind to CDK2-E inactivating it and preventing transition to S phase.
p21 is transcribed by p53 in response to stress signals.
p27 is degraded by SCF but SCF is degraded by APC/C during G1.

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10
Q

p53 p21 pathway

A

p53 is in tight control by mdm2 (mdm2 can be inhibited by ARF). In response to stress signals, p53 is phosphorylated so it cannot be targeted for degradation and translocates to the nucleus where it transcribed various target genes including p21. p21 then binds to CDK2-E inactivating it.

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11
Q

What does cdc25 do?

A

Phosphatase that activates CDK-cyclin complexes - cell cycle checkpoints use inactivation of cdc25 to regulate cell division

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12
Q

What does cdc20 do?

A

Regulatory protein that activates APC/C which degrades securin which is a separase blocker

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13
Q

What are the two types of genetic instability?

A

MIN - small subtle base changes leading to point mutations
CIN - continuous large scale loss or gain of whole chromosomes or parts of chromosomes. Associated with errors in chromosome segregation

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14
Q

What can cause MIN?

A

Environmental mutagens
Damage to DNA from intrinsic cellular metabolism (ROS)
Errors in DNA replication

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15
Q

Whatare the three types of DNA damage?

A

Breaks in DNA backbone
Loss of bases
Chemical modification of bases

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16
Q

Mismatch repair

A

Mismatch proofreading proteins (MutS, MutL, MutH) bind to DNA and scan it. A nick is detected in the new DNA strand. The new strand is removed and DNA synthesis makes a new strand.

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17
Q

Nucleotide excision repair

A

Helix distorting adduct is recognised, cleavage of DNA fragment. The gap is filled in by pol-delta or epsilon, PCNA and RPA and closed by ligase.

18
Q

Base excision repair

A

Chemically altered base is sensed due to little helix distortion. DNA glycosylate cleaves away base. APE cleaves the corresponding deoxyribosylphosphate from the nucleotide backbone. Pol-beta and DNA ligase fill in the gap

19
Q

Double stranded break repair

A

1) Homologous recombination - double stranded break is recognised, nucleolytic processing by nucleases and helicases cleaves the DNA strands in opposite directions. The DNA then crosses over, this ensures error free repair. DNA polymerase and ligase cut and close the crossovers
2) Non-homologous end-joining - the DNA is stuck back together - error prone as it does not use homologous sequence. Involves loss of genetic material - often leads to loss of function because of shift

20
Q

What are 5 types of mitotic errors that lead to numerical CIN?

A

Defective chromosome cohesion (mutations in genes for cohesion complex)
Centrosome amplification (Multipolar spindle - uncoupling of centrosome duplication from cell cycle or failure to divide in mitosis)
Merotelic chromosome attachments (error in which a single kinetochore is attached to microtubules emanating from both spindle poles - Aurora B is turned on when there is not enough tension on microtubules and causes them to fall of but merotelic attachments provide some degree of tension so aren’t corrected - means chromosomes aren’t segregated properly)
Mitotic checkpoint defects (SAC, Aurora A, Aurora B)
Cytokinesis failure

21
Q

What is the Paint test?

A

Cancer ensues only if the exposure to the promoter follows exposure to the initiator and only if the intensity of exposure to the promoter exceeds a certain threshold. Cancer can also occur as a result of repeated exposure to the initiator alone. This was tested by painting initator and promoter onto animals skin.

22
Q

What is the Ames test?

A

The test uses a strain of Salmonella bacteria that require histidine in the medium because of a defect in a gene necessary for histidine synthesis. Mutagens can cause a further change in this gene that reverses the defect, creating revertant bacteria that do not require histidine. To increase the sensitivity of the test, the bacteria also have a defect in their DNA repair machinery that makes them especially susceptible to agents that damage DNA. A majority of compounds that are mutagenic in tests such as this are also carcinogenic and vice versa.

23
Q

What does myc do?

A

Myc is activated upon various mitogenic signals such as Wnt, hedgehog and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification, presumably through DNA over-replication.

24
Q

Inducing angiogenesis treatments

A

Angiostatin (Binds to angiomotin inhibiting EC migration, invasion and morphogenesis; binds to avB3 integrin antagonising the proliferative migratory and pro-survival signals; binds to c-met decreasing the activation of PI3K/Akt leading to release of suppression of apoptosis)
Endostatin (More potent than angiostatin; inhibition of VEGF leading to reduced endothelial cell survival, proliferation; MMP inhibition resulting in reduced endothelial cell invasion; maintenance of cell-cell adhesion by inhibiting VEGF driven relocalisation of B-catenin from cell-cell junctions; binding of a5B1 integrin to prevent integrin dependent endothelial cell migration; downregulation of PDGF mediated recruitment of pericytes)
Thrombospondin (Inhibitor of tumour growth; expression regulated by p53)
VEGF antagonists
Protease/integrin antagonists

25
Q

Enabling replicative immortality treatments

A

Telomerase inhibitors

26
Q

Sustaining proliferative signalling treatments

A

CDK4/6 inhibitors?
Hedgehog pathway inhibitors
Growth factor pathway inhibitors (Ras, Raf, MAPK, PI3K, Akt)

27
Q

Genetic instability treatments

A

Drugs targeting multipolar cells

Chemotherapy (damages DNA - apoptosis)

28
Q

Resisting cell death treatments

A

Upregulate TSGs such as p53 and PTEN
Inhibit anti-apoptotic proteins such as Bcl-2
Upregulate pro-apoptotic proteins such as bim, bid
Upregulate Smac/diablo

29
Q

Induction of invasion and metastasis treatments

A 
E-cadherin upregulation
Integrin antagonists (e.g. avB3)
Protease inhibitors (uPA/uPAR; MMPs)
30
Q

Deregulating cellular energetics treatment

A

Lactate dehydrogenase inhibitor (prevent aerobic glycolysis)

31
Q

Tumour promoting inflammation treatment

A

NFkB - Ikk inhibitors (may have immune related side effects)
TNF-a antagonist (many side effects)

32
Q

Evading growth suppressor treatment

A

DNA methyltransferase inhibitors

Upregultion of PTEN

33
Q

Evading immune destruction

A

Vaccination
Upregulation of target antigen expression (WT-1)
Eliminate immune suppressing factors, and enhance tumor-killing activities

34
Q

Function of src

A

Src is part of the focal adhesion complex. It is a non-receptor tyrosine kinase that has many functions including cell adhesion, growth, movement and differentiation. (prodominantly off in cells - cancer causes it to be constitutively active)

35
Q

Hedgehog effects

A

Activation of the Hedgehog pathway leads to an increase in Snail protein expression and a decrease in E-cadherin and Tight Junctions. Hedgehog signaling also appears to be a crucial regulator of angiogenesis and thus metastasis. Activation of the Hedgehog pathway leads to an increase in Angiogenic Factors (angiopoietin-1 and angiopoietin-2), Cyclins (cyclin D1 and B1)), anti-apoptotic genes and a decrease in apoptotic genes (Fas).

36
Q

How does chronic inflammation help cancer?

A

Tumours release chemical signals that lure macrophages and granulocytes. Once inside the tumour these cells secrete cytokines which initiate angiogenesis. Other cytokines encourage growth of a stroma against which the tumour rests. Other inflammatory molecules release free radicals to further damage DNA.
Inflammation might also produce the proteases that aid breakdown of basal lamina and loss of E-cadherins

37
Q

What are the 4 actions of p53?

A

Cell cycle arrest (senescence of return to proliferation)
DNA repair
Block of angiogenesis
Apoptosis

38
Q

What is the barcode model?

A

Things like level, localisation, modification and co-factors contribute a bar to the barcode which is read by p53 and causes a specific cellular response

39
Q

What are miRs and how does p53 modulate them to prevent cancer?

A

miRs are single stranded small RNA molecules encoded by our genome that regulate gene expression by inhibiting translation. miRs are transcribed in the nucleus, cropped by drosha, translocate to cytoplasm where they are diced by dicer, this makes small single stranded RNA which is taken up by RISC complex (this is what is needed to bind to RNA recognised by miR). This leads to rapid mRNA degradation - can be partial or complete (reduce level of translation or completely remove translation)
p53 induces transcription of miR34 which promotes apoptosis and senescence.
p53 represses miRs that block expression of anti-apoptotic and anti-proliferative proteins
p53 interacts with drosha facilitating conversion
(myc inhibits many miRs)

40
Q

Therapies targeting miRs

A

Make virus particles containing miR delivered to tumour

Block miRs - miR sponges (some miRs inhibit p53)

41
Q

How do cancer cells evade apoptosis?

A

Mutated or missing p53 gene or increasing the inhibitors of P53, or silencing the activators of P53
Inactivating Rb
Excessive amounts of anti-apoptotic proteins such as bcl2 and bcl xl
Produce less of the pro-apoptotic proteins such as Bax and Bak. This short-circuits the extrinsic death receptor apoptotic pathway.

42
Q

uPA/uPAR pathway

A

uPA synthesised as pro-uPA, cleaves plasminogen to plasmin which:
cleaves TIMP2 releasing inhibition of activates MMPs
Cleaves pro-MMPs to activate MMPs
Degrades glycoproteins allowing MMP access to collagen
These all lead to degradation of the ECM

Year 4 (6 decks)

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