Molecular regulation of health
and disease
Example question
Additional explanation
Important
terminology
Abbreviation/Terminology list
PD1 Programmed cell death A receptor that plays a role in self-tolerance of
protein 1 immune cells and suppressing T cell
inflammatory activity.
WB effect The Warburg effect A change in cellular metabolism seen in cancer
cells. Cancer cells prefer fermentation instead of
aerobic respiration even in the presence of O2.
Usually cells only use this metabolism under
anaerobic circumstances
Reducing Can donate one electron in a reaction
equivalent
ROS Reactive oxygen species Chemically reactive chemical species
(compound) containing oxygen. Relative
amounts of ROS indicate the metabolic needs of
the cell. ROS is a mode of cell signalling.
Anoikis Programmed cell death
mTORC1 mammalian target of A nutrient/energy/redox sensor and controls
rapamycin complex 1 protein synthesis.
Rapamycin Inhibits mTORC1 activity
TSC Tuberous sclerosis Plays a role in cell growth upstream of mTORC
complex
Rag GTPases Recruit mTORC1 to the lysosomal membrane in
response to nutrients
Rheb Ras homolog enriched in A GTP binding molecule that plays a role in
brain activating lysosomal mTOR
Angiogenesis Growth of new blood vessels from existing ones.
Tumours attract blood vessels to themselves by
releasing growth inducing hormones.
TCA Citric acid cycle a series of chemical reactions used by all aerobic
organisms to release stored energy through the
oxidation of acetyl-CoA derived from
carbohydrates, fats, and proteins
Hypoxia Lack of enough oxygen in a certain area
Respiratory chain a series of complexes that transfer electrons
from electron donors to electron acceptors via
reactions, and couples this electron transfer with
the transfer of protons (H+ ions) across a
membrane.
TNF Tumour necrosis factor a cell signalling protein (cytokine) involved in
systemic inflammation
DISC Death-inducing signalling a multi-protein complex formed by members of
, complex the "death receptor" family of apoptosis-
inducing cellular receptors
IAP Inhibitor apoptosis Inhibit programmed cell death
protein
MOMP Mitochondrial outer induced disruptions in the outer mitochondrial
membrane membrane and subsequent release of death-
permeabilization promoting proteins like cytochrome c
PTP Permeability transition a protein that is formed in the inner membrane
pore of the mitochondria under certain pathological
conditions. Opening allows increase in the
permeability of the mitochondrial membranes to
molecules. It can lead to mitochondrial swelling
and cell death through apoptosis or necrosis.
MPT Mitochondrial
permeability transition
BAX bcl-2-like protein 4 This protein is reported to interact with, and
increase the opening of, the mitochondrial
voltage-dependent anion channel, which leads to
the loss in membrane potential and the release
of cytochrome c.
BAK1 BRI1-associated receptor acts as anti- or pro-apoptotic regulators that are
kinase 1 involved in a wide variety of cellular activities
Ubiquitin affects proteins in many ways: it can mark them
for degradation via the proteasome, alter their
cellular location, affect their activity, and
promote or prevent protein interactions.
ATG complex AuTophaGy complex It is essential for the initial building of the
autophagosome and Cvt vesicles.
BECN1 Beclin-1 plays a critical role in the regulation of both
autophagy and cell death.
Atg proteins Autophagy-related Proteins that play a role in autophagy
protein
CSC’s Cancer stem cells
Cpt-1 Carnitine is a mitochondrial enzyme responsible for the
palmitoyltransferase I formation of acyl carnitines by catalysing the
transfer of the acyl group of a long-chain fatty
acyl-CoA from coenzyme A to l-carnitine. It is
rate limiting for fatty acid oxidation.
ECM Extracellular matrix a three-dimensional network of extracellular
macromolecules, such as collagen, enzymes, and
glycoproteins, that provide structural and
biochemical support to surrounding cells.
Oncogene ERBB2 erythroblastic oncogene B Amplification or over-expression of this
oncogene allows uptake of glucose despite
detachment from the extracellular matrix (which
usually leads to apoptosis)
AMPK 5' AMP-activated protein an enzyme that plays a role in cellular energy
kinase homeostasis, largely to activate glucose and fatty
acid uptake and oxidation when cellular energy is
low.
PPP Pentose phosphate A metabolic pathway parallel to glycolysis. It
, pathway generates NADPH and pentoses as well as ribose
5-phosphate, a precursor for the synthesis of
nucleotides
FOA Fatty acid oxidation mitochondrial aerobic process of breaking down
a fatty acid into acetyl-CoA
EGF receptors epidermal growth factor Activation leads to DNA synthesis and cell
receptor proliferation mechanisms
LDHA Lactate dehydrogenase A catalyses the inter-conversion of pyruvate and L-
lactate
Anaplerosis Replenishing of TCA cycle intermediates
Oncometabolite An oncometabolite is a metabolite whose
abnormal accumulation causes metabolic and
non-metabolic dysregulation and potential
transformation into malignancy.
2-HG 2-Hydroxyglutarate An example of an oncometabolite
EMT epithelial–mesenchymal A process cancer cells undergo. This is a
transition reversible process
Proteome the entire set of proteins that is, or can be,
expressed by a genome, cell, tissue, or organism
at a certain time.
GTPase guanosine family of hydrolase enzymes that bind to the
diphosphatease nucleotide guanosine triphosphate (GTP) and
hydrolyze it to guanosine diphosphate (GDP).
GEF&GAP Guanine nucleotide GEFs stimulate the release of GDP from GTPases.
exchange factor & GTPase GAP can bind to GTPase and terminate the
activating protein signalling event.
GDI GDP dissociation regulate the GDP-GTP exchange reaction of
inhibitors members of the rab family, small GTP-binding
proteins, that are involved in vesicular trafficking
of molecules (including GTPases) between
cellular organelles
Akt Protein kinase B a serine/threonine-specific protein kinase that
plays a key role in multiple cellular processes
such as glucose metabolism, apoptosis, cell
proliferation, transcription, and cell migration.
TSC Tuberous sclerosis The complex is a tumor suppressor
complex
GATOR1 GTPase Activating Protein (GAP) or Rag
HIF1 Hypoxia inducible factors transcription factors that respond to decreases
in available oxygen in the cellular environment
MYC a family of regulator genes and proto-oncogenes
that code for transcription factors.
LKB1 Liver kinase B1 Regulates cell polarity and functions as a tumour
suppressor.
LKB1 is a primary upstream kinase of AMPK.
MAX Rearrangement of dimers (e.g., Mad:Max,
Max:Myc) provides a system of transcriptional
regulation with greater diversity of gene targets.
IDH Isocitrate dehydrogenase Isocitrate dehydrogenases catalyse the oxidative
decarboxylation of isocitrate to 2-oxoglutarate
,Succinate/ has multiple biological roles as a metabolic
Fumerate intermediate being converted into fumarate by
the enzyme succinate dehydrogenase in complex
2 of the electron transport chain which is
involved in making ATP, and as a signalling
molecule reflecting the cellular metabolic state.
Ubiquination A process that labels proteins for degradation
HRE genes Hypoxia response orchestrates the cellular response to low O2
element genes levels
ACC Acetyl-CoA carboxylase The most important function of ACC is to provide
the malonyl-CoA substrate for the biosynthesis
of fatty acids.
PK Pyruvate kinase the enzyme involved in the last step of glycolysis.
It catalyzes the transfer of a phosphate group
from phosphoenolpyruvate (PEP) to adenosine
diphosphate (ADP), yielding one molecule of
pyruvate and one molecule of ATP.
PKM1/2 M1 and M2 are isoenzymes of PK
VDACs Voltage dependent anion
channels
FASN Fatty acid synthase
3BrPA 3 Bromopyruvate
IBS Irritable bowel syndrome
TLR Toll like receptor a class of proteins that play a key role in the
innate immune system. They recognize
structurally conserved molecules from microbes
LTA Lipoteichoic acid major constituent of the cell wall of gram-
positive bacteria
LPS Liposaccharides
H2S Hydrogen sulphide is often produced from the microbial breakdown
of organic matter in the absence of oxygen gas. It
is considered harmful
MUC2 oligomeric mucus gel- it is secreted from goblet cells in the epithelial
forming lining into the lumen of the large intestine
Lypd8 Secreted protein specifically required to prevent
invasion of Gram-negative bacteria in the inner
mucus layer of the colon epithelium, a portion of
the large intestine which is free of commensal
microbiota. Prevents invasion of flagellated
microbiota by binding to the flagellum of
bacteria
Beta defensins The beta defensins are antimicrobial peptides
implicated in the resistance of epithelial surfaces
to microbial colonization.
HD5 and HD6 Alpha defensins produced by Paneth cells
Reg3 Intestinal Paneth cells produce REG3 via
stimulation of TLRs by PAMPs. REG3 gamma
specifically targets Gram-positive bacteria
because it binds to their surface peptidoglycan
layer.
MAMP Microbe associated molecules can be referred to as small molecular
, molecular pattern motifs conserved within a class of microbes.
They are recognized by TLRs
NLRs Nucleotide Intracellular sensors of PAMPs that enter the cell
oligomerization receptors via phagocytosis or pores, and damage-
associated molecular patterns.
Nf-kappa-b NF-κB induces the expression of various pro-B induces the expression of various pro-
pathway inflammatory genes, including those encoding
cytokines and chemokines, and also participates
in inflammasome regulation.
PRR signalling Pattern recognition are germline-encoded host sensors, which detect
receptors molecules typical for the pathogens.
IL10 Interleukin 10 also known as human cytokine synthesis
inhibitory factor (CSIF), is an anti-inflammatory
cytokine.
IL23 Interleukin 23 Proinflammatory cytokine involved in Th17
maintenance and expansion
Th17 T helper 17 cells Proinflammatory T helper cells
IL17 Interleukin 17 Proinflammatory cytokine involved in the
induction of other proinflammatory cytokines
RISC RNA induced silencing a multiprotein complex that incorporates one
complex strand of a siRNA or miRNA. RISC uses the siRNA
or miRNA as a template for recognizing
complementary mRNA.
IBD Inflammatory bowel
disease
TER Trans epithelial resistance
CECAM6 Carcinoembryonic Cell surface glycoprotein that plays a role in cell
antigen-related cell adhesion and tumour progression
adhesion molecule 6
GWAS Genome wide association an approach used in genetics research to
study associate specific genetic variations with
particular diseases.
IECs Intestinal epithelial cells
TRIF TIR-domain-containing an adapter in responding to activation of TLRs. It
adapter-inducing mediates the rather delayed cascade of two TLR-
interferon-β associated signalling cascades
IL8 Interleukin 8 A chemoattractant for neutrophils
GLAT Gut associated lymphoid
tissue
APC Antigen presenting cell
M cells Microfold cell initiate mucosal immunity responses on the
apical membrane of the M cells and allow for
transport of microbes and particles across the
epithelial cell layer from the gut lumen to the
lamina propria where interactions with immune
cells can take place.
Dnmt3a/3b and De novo Can put a methyl group in DNA where there
Dnmt1 methyltransferase wasn’t one before
SAM S-Adenosyl methionine methyl donor in cytosine methylation, which is a
key epigenetic regulatory process.
HAT Histone acetyl transferase
,EDRF Endothelium derived
relaxing factor
NO Nitric oxide An endothelium derived relaxing factor
Cyclic GMP Cyclic guanosine signalling in one of the major mechanism
monophosphate through which the effects of Nitric Oxide are
mediated
PGI2 Prostacyclin inhibits platelet activation and is also an effective
vasodilator.
IL8 Interleukin 8 It induces chemotaxis in target cells, primarily
neutrophils but also other granulocytes, causing
them to migrate toward the site of infection. IL-8
also stimulates phagocytosis once they have
arrived.
MCP1 monocyte recruits monocytes, memory T cells, and
chemoattractant protein 1 dendritic cells to the sites of inflammation
produced by either tissue injury or infection.
ICAM Intracellular adhesion When activated, leukocytes bind to endothelial
molecule cells via ICAM and then transmigrate into tissues.
VCAM Vascular cell adhesion The protein mediates the adhesion of
molecule lymphocytes, monocytes, eosinophils, and
basophils to vascular endothelium.
VSMC Vascular smooth muscle
cell
eNOS Endothelial nitric oxide responsible for the generation of NO in the
synthase vascular endothelium from L-arginine
BH4 Tetrahydrobiopterin A cofactor for eNOS
Foam cell fat-laden M2 macrophages containing low
density lipoproteins
LDL Low density lipoprotein
HDL High density lipoprotein
IFN gamma Interferon gamma a cytokine that is critical for innate and adaptive
immunity against viral, some bacterial and
protozoal infections. IFNγ is an important
activator of macrophages and inducer of Class II
MHC molecule expression.
IL12 Interleukin 12 IL-12 is involved in the differentiation of naive T
cells into Th1 cells.
IL6 Interleukin 6 an interleukin that acts as both a pro-
inflammatory cytokine and an anti-inflammatory
myokine
IL1beta Interleukin 1 beta This cytokine is an important mediator of the
inflammatory response, and is involved in a
variety of cellular activities, including cell
proliferation, differentiation, and apoptosis.
IL20 Interleukin 20 transmits an intracellular signal through two
distinct cell-surface receptor complexes on
keratinocytes and other epithelial cells. IL-20
regulates proliferation and differentiation of
keratinocytes during inflammation, particularly
inflammation associated with the skin
IL1Ra Interleukin 1 receptor is a natural inhibitor of the pro-inflammatory
, antagonist effect of IL1β.
PPAR gamma Peroxisome proliferator- regulates fatty acid storage and glucose
activated receptor gamma metabolism. The genes activated by PPARG
stimulate lipid uptake and adipogenesis by fat
cells.
LXR alpha Liver X receptor alpha key regulators of macrophage function,
controlling transcriptional programs involved in
lipid homeostasis and inflammation.
ACAT1 Acetyl-CoA localized enzyme that catalyzes the reversible
acetyltransferase formation of acetoacetyl-CoA from two
molecules of acetyl-CoA
oxLDL Oxidized LDL
CD36 Cluster of differentiation Has a function in long chain fatty acid storage
36 and uptake
NCP1 and NCP2 Niemann-Pick disease, a putative integral membrane protein containing
type C sequence motifs consistent with a role in
intracellular transport of cholesterol to post-
lysosomal destinations.
Caveolin 1 Transports cholesterol from the ER to the plasma
membrane
ABCA1 ATP-binding cassette This transporter is a major regulator of cellular
transporter cholesterol and phospholipid homeostasis.
VSM Vascular smooth muscle
cells
vWF Von Willebrand factor a blood glycoprotein involved in haemostasis
CVD Cardiovascular disease
DNMT DNA methyltransferase
Sin3a complex Paired amphipathic helix a transcriptional regulatory protein.
protein
JHDM Hydroxylate methylated
lysine
LSD2 Lysine specific
demethylase
5-MeC 5 methyl cytosine a methylated form of the DNA base cytosine (C)
that regulates gene transcription and takes
several other biological roles.
H3K27me3 Repressive methylation
H3K9me2 Active methylation
DMRs Differentially methylated
regions
MBDs Methyl CpG-binding
proteins
HDAC Histone deacetylase
HMT Histone methyl
transferase
EGCG Epigallocatechin gallate A polyphenol with implications for epigenetic
medicine
,Theme 1
Part 1
Knowledge clips on cancer biology
Cancer has the highest death number in many countries.
There is more cancer in the Netherlands than in other EU countries, due to a lot of female smokers.
Most common cancers in Netherlands: prostate and breast cancer.
Incidence = number of new cases of disease
Death rate = number of deaths caused by disease scaled to population
Cases of melanomas are on the rise because more exposure to direct sunlight.
Some types of cancers are increasing, and some are decreasing, this is related to changing lifestyle.
Hallmarks of cancer:
- Sustaining proliferative signalling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
- Avoiding immune destruction
- Tumour-promoting inflammation
- Genome instability & mutation
- Deregulating cellular energetics
A cancer cell makes biomass and energy.
Atp is the most important energy factor and biomass is protein, dna and rna.
Altered metabolism contributes to cancer cell function.
Glycolysis = glucose is converted into pyruvate.
Pyruvate can be anaerobically converted into lactate or aerobically entering the TCA cycle.
Apart from glucose fatty acids are transported into the cell and in the mitochondria the fatty acid
oxidation pathway occurs. Products from this can enter the TCA cycle. In the mitochondria NADH and
ATP are produced.
Glutamine is the most important for amino acid in cancer cells. It is imported into the cell and turned
into glutamate. This can go into the TCA cycle or be turned into lipids.
Intermediates from the glucose to pyruvate pathways are precursors for DNA. Pentoposphates are
formed that are DNA precursors.
When a tumour cells grows the inside cells lose contact with blood vessels decreasing O2 availability.
,Before a tumour cell there can be a tumour initiating cell, or a dormant cancer cell. A later state can
be metastasis and invasion.
During proliferation: metabolic reprogramming to maximize biomass and energy
During survival: metabolic reprogramming to maximize alternative fuels and antioxidant defense
Reader
A tumour can be benign, pre-malignant or malignant or merely a lesion. A cancer is a malignant
neoplasm (type of abnormal/excessive growth). When a cell proliferates two daughter cells are
created, biomass is doubled: this is a metabolic challenge.
Metabolism in proliferating cells differs.
A tumour is malignant if it invades or metastasizes.
Cell transformation: the process of cell change in which a cell loses the ability to control its division
rate.
Cancer cells differ from normal counterparts in:
- They are immortal
- They display lower growth factor requirements.
- They are invasive and have invasive properties
Loss of contact inhibition
Loss of anchorage dependency
Less organized, more mobile surface proteins
Show an altered secreted protein profile. (more proteolytic enzymes, which facilitate
migration and invasion)
- Resistant to programmed cell death
- Altered nutrient and energy metabolism
Increased glycolysis rate
More negative surface charge of the cell membrane and sustained angiogenesis
Cancer cells are reprogrammed such that optimal growth of the individual cell is facilitated, but at
the expense of the organism to which the cancer cell belongs.
Part 2
Knowledge clips
Glucose metabolism in cancer cells was discovered by Warburg.
He put cancer cells in a dish, added glucose and measured pH. He also measured pressure changes in
the flask with the bacteria. The tumour will use glucose and oxygen. If you trap the released co2 you
can measure the amount of oxygen used.
Warburg first discovery: tumours have a high rate of lactic acid formation.
Pasteur effect: high oxygen inhibits glycolysis in yeast, the yeast switches from anaerobe to aerobe.
The anaerobe way produces lactic acid. Warburg thought that if there was oxygen glycolysis should
be aerobe and therefore there should not be lactic acid. However there was.
During fermentation to lactate 10 times more glucose is used than during respiration (glycolysis with
oxygen). So anaerobe is more costly.
Warburg thought mitochondria were broken in tumours due to anaerobic glycolysis in the presence
of O2. This is not true, mitochondria rely on respiration as well.
He thought tumour cells could be killed by lack of oxygen. This is also not the case. Oxygen actually
can be used to kill cancer cells.
Why do cancer cells need this Warburg effect? There are 4 hypotheses:
- Rapid atp synthesis. The Warburg effect increases access to a limited energy source. The
glycolytic pathway is 100x faster than in normal cells. It yields 200 ATP per time unit.
, - Biosynthesis. Proposal: promotes flux into biosynthetic pathways. Increased glucose
utilization is used as carbon source for anabolic processes needed to support cell growth. The
pentophosphates pathway produces nucleotides and NADPH which is used to neutralize
oxidants.
- Tumour microenvironment. Enhances disruption of tissue architecture and immune cell
evasion. The H+ the mitochondrion releases makes the cell more acidic and promotes
invasiveness. It takes glucose away from native immune cells.
- Cell signalling. Allows for signal transduction through ROS and or chromatin modulation. It
causes DNA to be wound more tightly.
Glutamine is an amino acid essential for cancer cell growth.
Glutamine can be turned into pyruvate by mitochondria whereas glycolysis happens in the cytosol.
Pyruvate can be turned into lactate.
Glutamine is important for reducing NAD+ and NADPH, for lipid synthesis or for making nucleotides.
Glutamate contributes to biosynthesis.
Glutamate can also be turned into lipids. It turns into citrate which turns into lipids like shown above.
In a normal tca cycle decarboxylation occurs. Here citrate is produced with CO2 as a by-product.
In the carboxylation pathway citrate is also produced however CO2 is no longer a by-product. You
use CO2 as a label and test which of the two happens.
When there is a lack of oxygen cancer cells experience hypoxia, here reductive carboxylation occurs.
Citrate will be formed and lipids will be generated.
Glutamate can be turned into lipids via two different routes: cytosolic or mitochondrial. The
mitochondrial one is reductive carboxylation.
