Cancer Flashcards
1
Q
Sensor Proteins
A
- Detect DNA damage
- Recruit other molecules to the damage site
- “Mark” the damage
- Ex:
- p53 - upregulate inhibitory molecules
- Cdc25 family - downregulate stimulatory molecules
2
Q
Carcinogenesis
A
The overall sequential transition from a normal cell to a malignant one is called the multistep process of carcinogenesis.
- Cells acquire cancer promoting mutations through spontaneous and environmentally-induced DNA damage.
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3
Q
Genes involved in Carcinogenesis
A
Generally encode products which:
- Directly regulate cell proliferation
- Involved in the repair of damaged DNA
- Control programmed cell death or apoptosis
These “driver” mutations classified as:
- Proto-oncogene: promoting growth
- Tumor suppressor gene = inhibiting growth
- Landscaping genes = cell adhesion, susceptibility to apoptosis, etc
Many passenger mutations will develop.
By definition have no phyotypic consequence on the cell.
4
Q
Proto-oncogenes
A
The normal cellular forms of genes that are involved in regulating cell proliferation.
5
Q
Oncogenes
A
Mutated, cancer causing forms of proto-oncogenes.
- promotes cell growth
- gain-of-function mutation in most cases
- increased function can be due to:
- increased function of the gene product
- decreased degradation
- altered gene expression pattern
- changes in the gene product’s function
- single allele required to contribute to tumor formation
- works in a dominant manner within the cell
- usually lethal, rarely inherited, so do not show an inheritance patter
- result from somatic mutations
- many different genes can encode oncoproteins such as:
- growth factors or mitogens
- growth factor recetpros (HER2/neu)
- signal transducers (ras)
- transcription factors (myc)
- cell cycle regulators (cyclin D)
- pro-survival molecules (Bcl2)
6
Q
HER2/neu
A
- Gene encodes receptor tyrosine kinase called human epidermal growth factor receptor (HER)
- closely related to epidermal growth factor receptor
- Overexpressed through gene amplification
- Prompts ligand independent signaling via the Ras-MAPK pathway
- Drives cellular proliferation
- Overexpression of HER2 enables constitutive activation of growth factor signaling pathways
- Operates as an oncogenic driver in breast cancer
- Acts as both a biomarker and target for therapy
7
Q
Ras
A
- small GTPases activated by guanine nucleotide exchange factors (GEFs)
- Ras turns on other proteins that ultimately result in transcription of genes involved in regulation of:
- cell growth
- proliferation
- differentiation
- mutations can lead to production of activated Ras proteins permanently locked into active form
- continually activate the MAP kinase pathway
- Leads to cell proliferation
- Represents the most common type of mutation in an oncogene
8
Q
Cyclin D
A
- plays a critical role in growth factor signaling which drives cell cycle through the G1 checkpoint
- forms part of the Cyclin D-Cdk4/6 complex
- initiates the release of the Rb-dependent cell cycle-inhibitory “brake” on G1 checkpoint
- increased cyclin D function → decreased Rb activity
- Gain-of-function mutations of cyclin-D can occur through:
- gene amplification
- reciprocal translocation
- positions the gene near cis Ig heavy chain enhancer elements
- chromosomal inversion
- brings proto-oncogene close to a strong transcriptional control element
- CKIs can still inhibit the kinase action
- increased cyclin D expression drives the cell closer to growth factor independent function
9
Q
Myc
A
- Myc proto-oncogenes part of the early response genes transiently induced by RAS/MAPK path following GF stimulation
- Myc protein promotes transcription of many genes driving cell growth and proliferation
- Ex. cyclin D expression regulated by Myc
- c-Myc can be converted to oncogenic form through amplification or translocation
- Mitotic catastrophe likely in malignant cells with Myc hyperactivation if small ubiquitin-like proteins inactivated
- Pharm uncoupling of bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced accumulation might stop tumor growth
10
Q
BCR-ABL
(Philadelphia Chromosome)
A
-
ABL1 proto-oncogene encodes cytoplasmic and nuclear protein tyrosine kinase involved in:
- cell differentiation
- cell division
- cell adhesion
- stress response
- Loss of regulatory domain on ABL1 protein converts to oncogene
- can occur through reciprocal translocation
- results in the Philadelphia chromosome
- New gene encodes a chimeric gene - BCR-ABL - which exhibits unregulated activity
11
Q
Bcl-2
A
- Normal gene is an apoptotic regulator
- Oncoprotein activated by chromosome translocation
- Promotes cell survival
- Can inhibit effectiveness of chemotherapy
12
Q
Tumor Suppressor Genes
A
- Normally inhibits cell proliferation
- Act as brakes for cell cycle
- normally inhibits formation of tumors
- cancer often includes loss-of-function mutations
- only one functional copy need to stop cancer
- functions in a recessive fashion at cellular level
- mutations in genes inherited in dominant fashion
13
Q
Two-Hit Model
A
- only one functional copy of a tumor suppressor gene needed to prevent cancers
- both copies of the gene needs to be mutated for cancer to develop
14
Q
Retinoblastoma
(RB1)
A
- Those with heriditary form had one bad copy from parent
- a single hit caused loss of heterozygosity
- Loss of RB1 function resulted in loss of functional sequestration of transcription factor E2F
- E2F able to bind and promote production of cyclin E
- allows cell to transition through G1 checkpoint in absence of growth factors
15
Q
p53
A
- Transcription regulator that binds to both DNA response elements and transcription factors
- Alters transcription
- Halts the cell cycle
- Inhibits transition through the G1 and G2/M checkpoints
- Inhibits DNA replication through indirect action on DNA polymerase sliding clamp
- Can drive the cell to cycle arrest or apoptosis if DNA damage unrepairable
- Normally, p53 rapidly bound by Mdm2, a ubiquitin ligase
- Targets p53 for proteosomal degradation
- Rapid degradation allows other components like growth factors to control cell cycle
- When cell undergoes stress, p53 is phosphorylated and proteded from ubiquitylation
- DNA damage
- Hypoxia
- Exposure to certain cytokines
- Metabolic changes
- Viral infections
- Telomere shortening
- Oncogene-based deregulation
- Important role in cancer prevention:
- p53 mutations found in at least 50% of malignant cell populations
- heterozygotes for abnormal p53 have Li-Fraumeni familial cancer syndrome
- Some cancers upregulate Mdm2 expression
16
Q
BRCA-1 / BRCA-2
A
- BRCA proteins expressed in most cells
- Role in maintaining genome stability through repair of double stranded breaks
- Significant role in breast and ovarian cancer
- Mutations to these genes rare in sporadic breast cancer
- May be due to EMSY
- Binds and inhibits BRCA-2
- EMSY genes often amplified in sporadic breast cancer resulting in functional inhibition of BRAC-2
- May be due to EMSY
17
Q
Gatekeeper Genes
A
Directly control cellular growth, differentiation, and apoptosis.
- normal genes can:
- inhibit mitogenic signaling pathways
- inhibit cell cycle progession
- eneable genome stability
- provide proapoptotic functions
- mutations directly relieves normal controls
- promotes outgrowth of cancer cells
- Ex. p52, BAX
18
Q
Caretaker Genes
A
- Involved in maintaining the genetic integrity of the cell
- regulating DNA repair mechanisms
- chromosome segregation
- cell cycle checkpoints
- mutations result in genome instability
- increases frequency of alterations to gatekeeper genes
19
Q
Landscaper genes
A
Impact the intracellular and extracellular environment of the malignant cell.
- mutations lead to abnormal extracellular and intracellular environments
- contributes to carcinogenesis
- Ex. E-cadherin, inhibitors of pro-growth, von-Hippel-Lindau tumor suppressor protein in hypoxic response
20
Q
Epigenetics
A
- can visibly change the appearance of malignant cells
- hyperchromasia
- chromatic clumping
- vesicular nuclear chromatin
- Include changes in:
- DNA methylation
- histone modifiers (writers and erasers)
- histone readers
- chromatin remodelers
- microRNAs
- many cancers have global changes in DNA methylation and histone modifications
21
Q
Carcinogens
A
- radiation
- chemical carcinogens
- direct-acting vs indirect acting
- tobacco smoke
- aflatoxins
- made by some fungi
- associated with increased risk of liver cancer
- arsenic
- biological carcinogens
- HPV
- proteins bind to pRb, p53, and some CKIs
- hepatitis B & C
- Epstein-Barr virus
- HPV
22
Q
mTOR
(mechanistic target of Rapamycin)
A
The major nutrient sensor of the cell.
- coordinates signals for anabolic cell growth and proliferation
- upregulates transcription factors
- c-Myc
- HIF-1α (hypoxia-inducible factor 1 alpha)
- changes the transcriptome of the cell
- leads to reprogramming of glycolysis
23
Q
Cancer Cells
Metabolic Requirements
A
- NADPH
- electron donor in anabolic pathways
- Ribose-5-phosphase
- for nucleotide synthesis
- derived from PPP
- DHAP
- lipid synthesis for new membranes
- 3-phosphoglycerate
- precursor for synthesis of serine & glycine
- needed for entry of THF into carbon pool
- Both THF & glycine required for purine synthesis
24
Q
Reprogramming of Glycolysis
A
Works through mTOR
- GLUT-3 induction increases glucose uptake
- Embryonic isoform of hexokinase (HK-2) has lowest Km
- can trap glucose inside at much faster rate
- Embryonic isoform of pyruvate kinase (PKM2)
- sits at the end of glycolytic pathway
- rate of catalysis controls flux
- dynamically regulated between fast tetrameric form and slow dimeric form
- Induces expression of pyruvate dehydrogenase kinase
- Inhibits PDH complex
- Diverts pyruvate away from TCA
- Induces acetyl-CoA synthetase-2
- Makes up for loss of acetyl-coA from TCA
- needed for lipid synthesis
25
Q
PKM2
A
- Fast tetrametric form
- Favored in the presence of:
- Fructose-1,6-bisphosphate
- serine
- intermediates from purine synthetic pathway
- Glycolysis runs at full speed
- Favored in the presence of:
- Slow dimeric form
- Favored in the absence of anabolic intermediates
- Glycolysis backs up
- Pushes glucose-6-P into other pathways:
- PPP to generate NADPH and ribose-5-P
- lipid synthesis
- amino acid synthesis
26
Q
Glutamine
A
Cancer cells addicted to glutamine.
- directly used in purine and pyrimidine synthesis
- cMyc upregulates glutaminolysis proteins
- glutamine transporter
- glutaminase
- Glitaminolysis provides:
- glutamate
- aspartate
- CO2
- pyruvate
- lactate
- alanine
- citrate
- serves as anaplerotic substrates for TCA
- Provide carbon skeletons for biosynthesis
