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Cell regulation and Cancer > Simon Morley > Flashcards

Simon Morley Flashcards

1
Q

How are cancers classified?

A

According to the cell tissue type from which they arise

Carcinoma: Epithelial cells

Adeno-: gland

Sarcoma: muscle/connective tissue

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2
Q

Hayflick limit?

A

50 repetitions

Limit to replication of normal cells

Cells enter replicative senesence after this

Telomeres shorten as cells successively divide.

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3
Q

How can cells enter replicative sensescence?

A

Reach Hayflick limit

Become terminally differentiated

Experience DNA damage or other stressors

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4
Q

Cancer cells, crisis stage, telomerase?

A

Cells reach a crisis stage when telomeres become too short and chromosomes start losing DNA.

Genetic instability results, chromosomes can fuse, etc

Telomerase reactivated in 90% cancer cell lines.

Other cancer lines maintain telomeres through alternative methods!

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5
Q

Growth advantages possessed by tumour cells:

A

Increased rate of cell division

Increased genetic instability

Resistance to apoptosis (increased survival)

Increased clonal cell numbers (clonal expansion increases probability any clone can pick up further cancerous mutations)

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6
Q

Why is increased genetic instability useful for tumour cells?

A

Increases chance of generating advantageous heritable mutations (/epigenetic changes)

These changes are required to help them survive selection barriers such as low oxygen levels (secretion of VEGF –> angiogenesis)

or help them avoid apoptosis

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7
Q

Chronic Myelogenous Leukemia genetic defect?

CML

A

Chromosomal translocation between the long arms of chromosomes 9 and 22

Forms Philadelphia Chromosome

Bcr-Abl (an unregulated tyrosine kinase)

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8
Q

Burkitt’s Lymphoma pathophysiology?

A

Chromosomal translocation between chromosomes 8 and 14.

Specific to B-cells

Puts c-myc (transcription factor from end of chromosome 8) under control of strong promoter of antibody heavy chain. –>overproduction

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9
Q

What is the AMES test?

A

Test for mutagenic properties of sample material. E.g. new foods.

USES:

  • Sample, added to..

Culture of histidine-dependent salmonella (lack ability to make own histidine)

And homogenised liver extract (to see if metabolites are mutagenic, like aflatoxin)

If mutagenic: then more colonies mutate to become histidine independent and grow!

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10
Q

What is a tumour promoter?

A

A substance without intrinsic mutagenic/carcinogenic properties but amplifies carcinogenic effects of mutagenic substances.

Most effective when repeatedly applied.

(Perhaps activate expression of mutated silent genes.)

e.g. phorbol ester (mimics DAG, activates PKC)

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11
Q

What particular DNA damage caused by UVB exposure?

A

Pyrimidine dimers (C,T)

Errors in repair.

(xeroderma pigmentosum, inability to repair these dimers)

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12
Q

What are cytostatic and cytotoxic effects of chemo and radiotherapy?

A

Cytostatic: halted proliferation of cells

Cytotoxic: kills cells

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13
Q

Therapeutic index/ratio?

A

Maximum tolerated dose (toxic dose) (in 50% of pop)

divided by minimum effective dose (in 50% of pop)

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14
Q

How is a cell line established?

A

Cells in culture that survive the crisis period when the vast majority die

Over time, selective pressures transform the cell lines characteristics

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15
Q

Growth characteristics of cancer cells in culture?

A

Cancer cells are independent of anchorage requirements (grow on anything) and less dependent on growth factors.(some make their own growth factors)

They ignore density dependent inhibition. (grow on top of each other)

Altered morphology (less surface fibronectin, underexpression) disorganised cytoskeleton

Increased metabolic rate (more glucose transporters, increased protein synthesis)

Malignant tumours are invasive

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16
Q

Normal cell culture characteristics?

A

Dependent on anchorage to appropriate base material.

Dependent on growth factors to survive.

Density-dependent inhibition of growth.

**Flat morphology **with extended network of stress fibres on growing surface

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17
Q

What makes tumour cells invasive and motile?

A

Decreased fibronectin and e-cadherin. (reducing cell-to-cell contacts)

Collagenase expression

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18
Q

Hallmarks of cancer cells?

A
  • Self sufficiency in growth signalling
  • Insensitivity to anti-growth signals
  • Evasion of apoptosis
  • Limitless replicative potential (no hayflick limit)
  • Sustained angiogenesis
  • Tissue evasion and metastasis (decrease in e-cadherin, production of collagenase etc)
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19
Q

What is the Warburg effect?

A

Production of lactic acid by tumour cells

An incompletely explained switch to anaerobic metabolism even in the presence of oxygen.

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20
Q

What are 3 main families of retroviruses?

A

Spumaviruses (persistant infection, no pathogenesis)

Lentiviruses (slow viruses, can infect non-dividing cells–> useful in lab)

**Oncoviruses **(any oncogenic virus! not necessarily retrovirus)

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21
Q

How does Rous Sarcoma Virus cause sarcoma? (in chickens..)

A

Retrovirus. Oncovirus. (acutely transforming virus) Inserts its DNA into host genome, which for some reason includes viral version of Src (non-receptor tyrosine kinase, lacks regulatory pTyr527, last 19aa)

(Src can cause phosphorylation of vinculin and so debundling of actin filaments –> loss of cell structure, cell to cell adhesion)

(Src can activate Ras, and is short for sarcoma!)

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22
Q

Define an oncogene?

A

A “gain of function” mutant gene whose abnormal expression or altered gene product leads to a malignant phenotype!

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23
Q

Define a proto-oncogene?

A

Cellular homologue from which oncogene derived

(often called c- something, for cellular version, normal version)

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24
Q

Define a tumour suppressor gene:

A

A gene encoding a protein that restricts cell growth.

A **loss of function **mutation in a tumour suppressor contributes to cancer cell formation.

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25
Q

Describe ways proto-oncogene can become oncogene?

A

Mutation (point or deletion) in coding sequence causing overactive protein (e.g. Ras)

**Gene duplication/amplification **resulting in **overexpression of normal protein **(e.g. jun, transcription factor)

Chromosome rearrangement that places a normal coding sequence next to a strong promoter resulting in overexpression (e.g. c-myc next to Ab heavy chain promoter in Burkitts lymphoma, 8 & 14)

Chromosome rearrangement that creates an abnormal, hyperactive fusion protein. (Such as Bcr-abl in CML 9,22)

26
Q

What is an immediate early gene?

A

A family of genes that are rapidly and transiently upregulated following an external stimulus such as growth factors, hormones or stress.

27
Q

4 main groups of (proto)oncogenes?

A

Growth factors

(Growth factor) Receptors

Transducers (e.g. src, Ras, Grb-2, Raf)

Transcription factors (e.g. myc, jun)

28
Q

How does a normal quiescent cell return to cell cycle?

A

2 waves of signalling:

1) Competence factors (typically growth factors) [6hours!]
2) Progression factors (e.g. insulin, IGF-1) [4hours and requires right nutrients]
3) Must also overcome inhibitory signals! (e.g TGFbeta which suppresses c-myc through p15 and p21)

29
Q

How are SH2 domains specific to different phosphotyrosines?

A

THey bind only particular phosphotyrosines in the context of their specific surrounding peptide motif.

30
Q

What is sis?

A

A growth factor/mitogen class oncogene.

v-sis found in simian sarcoma virus, an acutely transforming retrovirus, oncovirus.

Produces PDGF beta chain, accompanied by ‘env’ a viral protein signal for secretion.

Therefore can activate PDGFR, a RTK, by autocrine loop –>proliferation

31
Q

What is Erb-B2?

A

Aka: HER2 (human epidermal growth factor receptor2) (breast cancer) oncogene.

Growth factor receptor/RTK class oncogene.

Constituently active RTK (dimerises), lacking ligand binding domain.

32
Q

Domains/components of src?

A

Unique domain (unique to Src family) Myristoylated (n-terminus) attaches it to membrane.

SH2 domain

SH3 domain

Kinase domain (SH1)

Phosphorylated at tyrosine 527 (c-terminus) in basal state. (this interacts with own SH2 domain)

33
Q

How to activate c-src?

A

Association of src SH2 domain with activated RTK.

This displaces src’s **pTyr527, allowing it to be desphosphorylated **(by PTPase)

Src opens up, exposing:

Tyrosine 416 in kinase domain to be autophosphorylated!

src fully active.

34
Q

What is different between v-src and c-src?

A

v-src, found in (rous sarcoma virus) lacks last 19aa at c-terminus

Therefore lacks regulation by pTyr527

src remains in open conformation, allowing phosphorylation of Tyr416 and so constituitive activation

35
Q

95% of pancreatic carcinomas are associated with what signalling malfunction?

A

Uncontrolled Ras activity!

36
Q

How is Ras associated with the plasma membrane?

and how is Src?

A

Ras is farnesylated (CaaX motif at C-terminal)

Src is myristoylated (N-terminal glycine, amide bond)

37
Q

3 proteins that regulate Ras?

A

GAP: GTPase activating protein

GEF (sos): displaces GDP to allow GTP binding

GDI (guanine dissociation inhibitor): prevents GDP dissociation

38
Q

2 ways Ras is connected to RTKs?

A

via Grb-2 and sos/GEF

or via Src which phosphorylates SHC, so grb-2 binds phosphorylated SHC.

39
Q

Role of PTPase in activating src?

A

Protein tyrosine phosphatase.

contains SH2 domain, attaches to RTK.

Dephosphorylates Y527 on src, after its release from src’s SH2 domain

40
Q

PI3-Kinase components:

A

p85 regulatory SH2 containing subunit recruited to RTKs

p110 lipid kinase subunit (phosphorylates inositol lipids at 3 position)

[Requires Ras-GTP for full activation!]

41
Q

Function of PTEN?

A

Dephosphorylates inositol lipids at 3 position such as PIP3

works against action of PI3K

Acts as tumour suppressor gene

42
Q

Dual specificity kinase?

A

MEK is a threonine and tyrosine kinase!

phosphorylates ERK/MAPK to activate it (on -TEY- activation loop)

43
Q

How is MAPK deactivated?

A

Dephosphorylated by phosphatases

MKP-1, MKP-2 etc

44
Q

How is c-jun, transcription factor, activated?

A

By JNK (Jun N-terminal Kinase) phosphorylating it near the n-terminal

And by dephosphorylation mediated by PKC (obvs via a nuclear phosphatase)

Without JNK phosphorylation jun still binds DNA, but has no activity

45
Q

How does jun dimerise?

A

Leucine zipper region, can form homodimer or heterodimer (e.g. with c-fos or ATF2)

46
Q

Action of c-jun/AF2 heterodimer?

A

Both components activated by phosphorylation (e.g. by JNK)

Increase c-jun production!

(in response to growth factor/stress signals)

47
Q

What is AP-1?

A

Heterodimer of c-fos and c-jun.

Causes increased expression of cell cycle progression genes. (such as c-myc!)

binds to GTAC/TGAC sequences

48
Q

What does c-myc do?

A

Expressed in response to AP-1

Transcription factor:

Forms heterodimer with Max (through leucine zipper)

Acts as activator to bind to E-box (enhancer box) sequences in promoter regions.

Increases transcription of genes including:

  • cyclin D1 (cell cycle progression)
  • ubiquitin ligase (protein turnover)
  • Transcription factors such as E2F
49
Q

Role of Max/max homodimers?

A

Present in resting state of cell when myc levels are low.

Only repress gene expression.

50
Q

What is the restriction point in the cell cycle?

A

A point in G1 phase of the cell cycle at which the cell becomes committed to the cell cycle [replication] (after which it no longer requires extracellular signals)

Phosphorylation of **Rb **(tumour supressor) required for progression

51
Q

Role of Rb? (retinoblastoma protein)

A

Nuclear phosphoprotein

Arrests cell cycle at G1/S boundary (restriction point)

In unphosphorylated basal state binds transcription factor E2F, inhibiting it.

Phosphorylation of Rb by CDKs (with cyclins D then E)

52
Q

Role of CAK?

A

Activates CDK/cyclin complex by phosphorylation

(Is itself a CDK: CDK7)

53
Q

Role of cyclin dependent kinase inhibitor proteins?

p16, p21, p27?

A

p16: binds CDK4 to prevents its association with cyclin D!

p21: binds CDK/cyclin complexes to inhibit them

p27: binds complexes or cyclin D itself

[all can be sent for proteasome degradation by phosphorylation]

54
Q

What is p53 and what activates it?

A

(tumour suppressor) p53 is a transcription factor that binds to a 10bp DNA sequence to control expression of pro-apoptotic, anti cell cycle progression, or anti-genome instability genes!

55
Q

3 genes regulated by p53 transcription factor

A

Pro-apoptotic bax

**GADD45 **(growth arrest and DNA damage inducible protein) prevents genome instability

**p21: CDK inhibitor **(inhibits phosphorylation of Rb)

56
Q

How is apoptosis regulated?

A

Bcl2 family proteins regulate mitochondrial membrane permeability. Some are pro-apoptotic, some anti-apoptotic.

Pro-apoptotic: Bax, BAD etc

Anti-apoptotic: Bcl-2 etc

57
Q

Ligand induced apoptotic pathway?

A

Fas ligand binds to Fas receptor. (trimerises)

Death domains on Fas recruit caspase 8 and activates it.

Activates caspase cascade (proteases!)

Casp-8 cleaves casp-3 into its active form

(Casp-8 also damages mitochondrial membrane to release cytochrome-c, which activates Casp-9 which also activates casp-3)

58
Q

What are caspases?

A

Proteases in a cascade, cleave proteins at Aspartate containing motifs.

Orchestrate apoptosis!

59
Q

What is c-flip?

A

c-flip prevents the activation of caspase-8 by Fas death domains

60
Q

How could a lack of growth factor stimulation lead to apoptosis?

(via PKB)

A

Activation of PKB/Akt in response to growth factor stimulation:

PKB phosphorylates BAD, allowing 14-3-3 proteins to bind phosphorylated BAD.

In the absence of PKB phosphorylation, unphosphorylated BAD inactivates the anti-apoptotic Bcl-2, by forming a heterodimer with it, preventing it from halting apoptosis.

61
Q

How can tumour cells become resistant to Fas induced apoptosis?

A

Decreased Fas receptor expression

Expression of soluble Fas

Increased expression of c-flip

Decreased caspase 8 expression

Increased Bcl2 or decreased Bax/Bak/BAD

62
Q

Which transcription factor promotes c-fos?

A

Elk-1/TCF (when phosphorylated by ERK) and interacting with SRF at SRE c-fos promoter.

Cell regulation and Cancer (3 decks)

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