week 9 Flashcards
interphase (90% of the cell cycle) is divided into subphases (4)
G1 - 1st gap
S - synthesis
G2 - 2nd gap
G0 - resting phase
what happens in G1
first gap phase
- prep phase prior to cell entering DNA synthesis phase
- requires nutrients and growth factors - RNA protein, lipid and carb synthesis
many organelles are duplicated (NOT dna yet)
duration - variable
what happens in S phase
- DNA and chromosomal protein synthesis occurs
duration- approx 7-8 hours in a typical mammalian cell with a 16 hour cycle
cell is now committed to cell division
- no growth factors needed
- DNA replication occurs here creating 2 identical daughter genomes
what happens in G2
second growth phase
- interval between DNA synthesis and mitosis
- enzyme, protein and ATP synthesis occurs
duration - lasts aprox 3 hours
what happens in M phase
- mitotic phase
Cell undergoes mitosis and then cytokinesis
duration 1-2 hours
what happens in G0
- State of withdrawal from cell cycle
-Cell is neither dividing nor preparing to divide - Instead, the cell is “doing its job” - performing it’s
function within the tissue - Common for differentiated cells
- Examples of cells in G0:
- Hepatocytes, neurons
what are the three features of biochemical switches
- Generally binary (on/off) to launch an event in a
complete & irreversible fashion - Robust & reliable
* Contains back up mechanisms to ensure efficacy under
variable conditions & if some components fail - Adaptable & modified to suit specific cell types
- Responds to specific intracellular or extracellular signals
- Cyclin dependent kinases (Cdks) – more to come
what are the checkpoints / transitions in the cell cycle
Points in the eukaryotic cell division cycle where
progress through the cycle can be halted until conditions
are suitable for the cell to proceed to the next stage
what are the major regulatory transitions in the cell cycle checkpoints
- Start Transition (aka G1/S)
- G2/M transition
- Metaphase-to-anaphase transition (aka M-to-A)
what is the rate limiting and committing step of the cell cycle
G1/S
what is the key cell cycle control system
cyclin dependant kinases
cdks are responsible for ……. in ….. of intracellular proteins that initate/regulate the major events of the cell cycle
cyclical changes
phosphorylation
Cdks are controlled by a group of proteins called
cyclins
cyclical changes in cyclin protein levels result in the cyclic assembly and activation of ……… at specific stages of the cell cycle
cyclin cdk complexes
what are the 4 classes of cyclins that form specific complexes with Cdks
- G1 cyclins : D cyclin
- G1.S cyclins : Cyclin E
- S- cyclins : cyclin A
- M cyclins : Cyclin B
G1 cyclins : D cyclin
- forms complex with Cdk4 or Cdk 6
- involved in G1 phase of the cell cycle, needed for initiation of transcription of G1/S cyclins to help promote passage through start transition
G1.S cyclins : Cyclin E
- forms a complex with Cdk2
- bind Cdks at the end of G1 and help trigger progression through the start transition
- levles decrease in S phase
S- cyclins : cyclin A
- forms complex with Cdk1 and Cdk2
- bind cdks after progression through start transition and helps timulate chromosome duplication during S phase
- levels remain evela
- M cyclins : Cyclin B
- forms complex with Cdk1
- binds Csks to stimulate entry into mitosis at the G2/M transition
- levels decrease in mid mitosis
how do cyclin Cdk complexes work
Cyclin protein does not simply activate its Cdk partner, but also directs it to a specific target protein
APC/C is the
anaphase promoting complex
aka cyclosome
- Member of ubiquitin ligase family of enzymes (labeling for destruction in proteasomes)
- Used to stimulate proteolytic destruction of specific regulatory proteins
Target proteins: securin, M-cyclins, S-cyclins
Growth factors are required in the …. phase
G1
Growth factors bind to specific receptors to
stimulate cellular growth and proliferation
Early response genes are
usually transcription factors
activated by OA
Delayed response genes are
usually Cdks, cyclins, or other proteins needed for cell division
in response to binding a growth factor …….
Cyclin D and then E are transcribed and translated
Cyclin D can form complexes with
Cdk4 and Cdk 6
- Call the G1-cdk complex
Cyclin E can form complexes with Cdk2
Called the G1/S-cdk complex
Active G1-cdk and G1/S-cdk complexes allows
progression through the start checkpoint
Active G1-cdk (and G1/S-cdk)
complex will target a protein
called
RB and phosphorylate
it.
RB functions as a
a transcription co-repressor
Hyperphosphorylation of RB will
inactivate RB
Inactive RB then releases a transcription factor ….
E2F,
allowing transcription to proceed
In early S phase, cyclin D (G1-cdk complex) and E
(G1/S-cdk complex) are
targeted for destruction
This also promotes progression through the S phase of the cell cycle
Active S-cdk complex allows progression through
the S phase of the cell cycle
What was the S-cdk complex?
cyclin A
What is occurring during the S phase of the cell cycle?
synthesis of DNA
during G2
- S-Cdk complex levels are still high in G2
-* M-cyclin levels begin to rise
- Form a M-Cdk complex
M-Cdk complex is needed to pass through the G2/M
checkpoint
At the end of G2, the S-cyclins are destroyed
We need to be able to control the activity of Mcyclins so that
mitosis doesn’t start too soon
Once the M-Cdk complex is assembled, it is
immediately
inhibited via phosphorylation
When the cell is ready for mitosis to begin, the M-Cdk
complex is
de-phosphorylated
Before progressing to anaphase and then to telophase, we reach our final checkpoint
Metaphase-to-anaphase (M-to-A)
checkpoint
in the metaphase to anaphase checkpoint Instead of a cyclin-cdk complex being used to
progress through the M-to-A checkpoint, instead we
used
regulated proteolysis
APC/C complex targets a protein called …… by
ubiquitylation for destruction by a proteosome
securin
Securin is an …..
that protects protein linkages that
hold …..
together in early mitosis
inhibitory protein
sister chromatin pairs
Destruction of securin activates a …… that separates the sister
chromatids allowing progression
to ….
protease
anaphase
At the end of mitosis, the M-cyclins are also
targeted for …..
destruction by APC/C
Destroying these cyclin APC/C inactivates most …. in cell
Then, many proteins phosphorylated by ….from S
phase to early mitosis are ……by
various ….. in the anaphase cell
Cdks
Cdks
dephosphorylated
phosphatases
In unfavourable conditions, the cell cycle can be paused
at any of the main checkpoints, what checkpoints?
progession through G1
entry into M
progression through M to A
Progression through G1 is delayed if:
- DNA is damaged by radiation, chemicals, or errors
- Absence of nutrients or growth factors
- Abnormal cell size
Entry into M is prevented when
- DNA replication is not complete
- Presence of DNA damage
- Abnormal cell size
Progression through M-to-A is prevented if
Chromosomes are not properly attached to mitotic spindle
what is CKI
binding of cdk inhibitory protein
- inactivates cyclin Cdk complex
- binding stimulates rearrangement in structure of Cdk active site
- primarily used by cells to govern the activities of G1/S and D-cdks early in the cell cycle
what are the three important CKIs
p16 inhibits
p21 inhibits
p27 inhibits
p16 inhibits
- CyclinD-cdk4 & CyclinD-cdk5 (G1-cdk complex)
p21 inhibits
-CyclinE-cdk2 (G1/S-cdk complex)
- CyclinA-cdk2 & CyclinA-cdk1 (S-cdk complex)
-Cyclin B-cdk1 (M-cdk complex)
p27 inhibits
- CyclinA-cdk2 & CyclinA-cdk1 (S-cdk complex)
- CyclinE-cdk2 (G1/S-cdk complex)
- Cyclin B-cdk1 (M-cdk complex
what are the two main tumour suppressor genes
p53
RB
what does p53 recognize
- Recognizes and binds damaged
DNA - Unstressed cells have lower levels of p53 since it will be bound by a protein called Mdm2 and be
degraded
what does RB recognize
Generally found in active form
* Can also recognize damaged DNA
In the presence of DNA damage, p53 will be
phosphorylated, releasing ……
p53 will not be ….
Mdm2
degraded
Active p53 binds DNA
and promotes the
transcription of …
p21
p21 binds the G1/S-cdk
complex, inhibiting it.
An inactive G1/S-cdk
complex will pause
the cell cycle at the
__?__ transition
RB in the presence of a growth suppressor signal or DNA damage
p16 is transcribed; p16
inhibits the G1-cdk complex,
which was needed to
inactivate RB
RB remains activated and
bound to E2F
- * No transcription of G1/S- cyclins or S-cyclins
- * Cell cycle is paused at start transition
what is contact inhibition
The cell cycle progression can
also be inhibited due to contact with:
other cells
- density dependant
inhibition
a basement membrane or other matrix component
- anchorage
dependance
*** regulated with cadherins and Beta-catenin
pathway
describe PI3K-Akt-mTOR C pathway in the cell cycle
Akt can promote cell cycle progression by:
* Akt activates/increases:
Cyclin A —> activation of CDK-1
Cyclin D ——> activation of CDK-4/6
Akt decreases/inactivates:
- p21 and p27
what are the three types of point mutation
substitution
insertion
deletion
substitutions can be
transitions (A , G or C,T) and transversions (purine for pyrimidine bases
Insertions or deletions of single nucleotides can lead to
frameshift mutations – all of the triplets are off by one
These are often called “frame-shifting indels”
* Often results in total loss of function of the protein:
▪ “O” blood type results from a frameshift mutation and
loss of function of the red blood cell antigen
▪ Tay-Sachs disease
If a multiple of three nucleotides are inserted or deleted, then the
reading frame is preserved
One nucleotide deletion
frameshift
Protein is no longer
functional
Three nucleotide deletion –
non-frameshift, but
loss of an
amino acid
what are the two types of point mutations
silent or conservative missense
nonconservative missense
what is an example of non conservative missense
sickle cell anemia
what does the sickle cell anemia surprisingly protect against
malaria
-RBCs that have some sickle-cell hemoglobin are not good hosts for the parasite that causes sickle cell disease –
thus the trait (heterozygote patient) is protective
▪ However, the homozygote (all hemoglobin
is sickle-cell hemoglobin) is more vulnerable to the disease than rest of the
population
mendelian disorders
Due to mutations in single genes that have large
effects
Most of these have relatively small effects on phenotype
Penetrance
how likely the mutated gene is to be expressed
So, if something is autosomal dominant but has a 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype
Disorders due to insufficient production of an enzyme
tend to be recessive
enzymes are specific therefore tend to be more severe
what is Marfan syndrome
- disorder of connective tissues, manifested
principally by changes in the skeleton, eyes, and cardiovascular system
-Epidemiology: prevalence of 1 in 5000
- Etiology:
▪ Disorder due to a defect in gene for fibrillin-1 - 75 – 85% are familial; the rest are new mutations
- Autosomal dominant
▪ chromosome 15
▪ 600 distinct mutations – most are missense
what is the Pathophysiology of Marfan syndrome
▪ Fibrillin is an important component of elastic connective
tissue, provides a “scaffold” for elastic fibre deposition
▪ Loss of fibrillin-1 explains many findings
* i.e. aneurysm formation, ligamentous laxity, defects in
eye structure
* Others are more difficult to explain
* Thought that increased skeletal growth is due to
increased bioavailability of TGF-beta, which is affected
by fibrillin levels (TGF-beta can also impact smooth
muscle development)
what are the Clinical findings of Marfan syndrome
Tall, with very long extremities and lax ligaments
▪ Dislocation of the lens
▪ Cardiovascular changes:
* Mitral valve prolapse – malformed and “weak” heart
valve
* Weakness in the muscular layers of the aorta, which
can lead to aortic valvular incompetence and
development of serious aneurysms
▪ Variable expressivity – some individuals may be lacking
certain clinical findings
* i.e. skeletal findings with no ocular findings
* Prognosis: Variable, main cause of mortality and morbidity are
aneurysms and valvular defects
▪ Surgical repair of aneurysms, heart valves
Autosomal recessive disorders
Largest category of Mendelian disorders
The expression of the defect tends to be more uniform than in
autosomal dominant disorders.
▪ Complete penetrance is common.
▪ Onset is frequently early in life.
▪ Although new mutations associated with recessive disorders do
occur, they are rarely detected clinically, since the individual with
a new mutation is an asymptomatic heterozygote
▪ Many of the mutated genes encode enzymes
* In heterozygotes, equal amounts of normal and defective enzyme
are synthesized
* Usually the natural “margin of safety” ensures that cells with half
the usual complement of the enzyme function normally
Consequences of Enzyme Defects
Accumulation of a substrate
Blockade of a metabolic pathway
Failure to inactivate another enzyme or substrate
Lysosomal storage diseases
Lysosomal storage disorders can be from a range of
problems with lysosomal enzymes:
▪ Lack of the enzyme, leading up to a build-up of a
substrate within a cell that is toxic
▪ Misfolding of the lysosomal enzyme
▪ Lack of a protein “activator” that binds to the substrate
and improves the ability of the enzyme to act on it
Pathophysiogy of lysosomal storage diseases
- In the example shown, a complex
substrate is normally degraded by a
series of lysosomal enzymes (A, B,
and C) into soluble end products - deficiency or malfunction of one of
the enzymes (e.g., B) → incomplete
catabolism → insoluble
intermediates that accumulate in
the lysosomes → “primary
storage” problem
▪ huge, numerous lysosomes
interfere with cellular function - secondary storage problem = toxic
effects from defective autophagy
▪ autophagy = “cellular
housecleaning”
Gaucher Disease
- Most common lysosomal storage disease
▪ Between 1 in 20,000 and 1 in 40,000 live births
▪ Autosomal recessive inheritance - Defect in the gene for glucocerebrosidase
▪ Enzyme cleaves the - glucose residues from ceramide, found in cell membranes
- glucosylceramide accumulates in lysosomes
▪ Metabolites accumulate mainly within macrophages and
other phagocytic cells as they phagocytose dying cells
and metabolize the membranes - This can lead to the activation or loss of function of the
phagocytes
Gaucher Disease type 1 vs type 2
Type I – involves organs outside the
central nervous system – 99% of cases
▪ Findings are mostly within the spleen
and bone
* Enlargement of the spleen and liver
* Weakened bones → frequent
fractures
▪ Often relatively mild course
- Type II – involves the CNS as well as
other organs
▪ Hepatosplenomegaly and rapid
neurological deterioration, with
death in early childhood
▪ CNS macrophage activation →
production of toxic signals by
macrophages → neuronal death
An affected male does not transmit the disorder to his
….., but all …. are carriers.
sons
daughters
Sons of heterozygous women have a … in …. chance of receiving the mutant gene
1 in 2
A male with a mutant allele on his single X chromosome is ……..
= hemizygous for the allele
X-linked recessive inheritance is
transmitted by healthy heterozygous female carriers to affected males
affected males to their obligate carrier daughters
Hemophilia A is the
Loss of function of a coagulation factor necessary
for clotting
▪ Affects over 20,000 men in North America
▪ Different mutations confer different bleeding risk –
thousands of mutations have been identified with
variable impacts on coagulation
clinical features of hemophilia A
▪ Bruising and prolonged bleeding with minimal trauma
▪ Mucosal bleeding, hematomas in joint spaces
(hemarthrosis)
proband
The person being “examined” (usually the one with a genetic condition)
Position of the proband in the family tree is indicated by
an arrow
A complete family history is then taken “centered”
around the
proband
autosomal dominant in a pedigree
- Frequent
appearance of
the disease
throughout
generations
may not show
typical 50%
chance of
transmission
(remember
reduced
penetrance)
autosomal recessive in a pedigree
The risk of
autosomal
recessive
disorders
manifesting
increases if there
is consanguinity
X-linked recessive in a pedigree
Only males appear affected
Trait is never passed from
father to son
DNA replication happens during what phase
S
each daughter strand cell will inherit a …… containing ….. and …..
DNA double helix
1 original strand
1 new strand
DNA four main steps
strand separation
primer creation
DNA replication
primer removal
what two protiens are needed to open up the DNA helix
DNA helicase
single stranded binding proteins
what bonds do DNA helicase break
H bonds between complimentary base pairs
what is the purpose of single stranded binding pairs
stablility
what are the two limitations of DNA polymerase
DNA polymerase can only add nucleotides to an existing strand of DNA
only works in 5- 3 prime direction
what will a primer be used for DNA polymerase ?
serves as a base paired chain on which to add new nucleotides
leading strands are synthesized
continuously
the lagging strand is synthesized
discontinuously
- direction of polymerization is opposite to chain growth
how many primers do we need for lagging strands
one for each okazaki fragment
RNA primers are removed by
DNA repair system and then are replaced with DNA
DNA ligase …
joins the 3’ end of the new DNA fragment with the 5’ end of the previous fragment
seals the gap
what fixes supercoiling
DNA topoisomerase
- breaks phosphodiester bonds
- allows DNA to rotate freely
- bonds will reform as the enzyme leaves
in addition to DNa replication, …. must also be synthesized so that newly replicated DNA can be packaged into nucleosomes
histones
histone synthesis happens during what phase of the cell cycle
S
what is the DNA polymerase activity
- takes place prior to a new nucleotide being covalently added to the growing daughter chain
- correct nucleotide has a higher affinity for the DNA polymerae than an incorrect nucleotide
- more energetically favourable to add the correct nucleotide
what is exonuceolitic proofreading
occurs right after an incorrect nucleotide has been covalently added to a growing daughter chain
- will not provide an effective 3’OH end for the DNA polymerase to add on the next nucleotide
- separate catalytic site on DNA polymerase will initate DNA polymerase to move in a 3’ to 5’ direction, clipping off any unpaired or mispaired residues
using proofreading exonuclease
what are telomeres
specialized nucleotide sequences at the end of the chromosome
- many tandem repeats
what are telomere sequences recognized by
telomerse
- can replenish sequences each time a cell divides
- activity of telomerase varies based on the cell type
replicative cell senescence
cell has withdrawn from the cell cycle and is no longer dividing
telomerase recogonized the … of an exisiting ……. repeat on the parent strand and will ….. it in the …. direction
tip
telomere DNA
elongate
5’ to 3’
what does telomerase use as a template
RNA template
- reverse transcriptase
what is a centrosome
- protein organelle
- consists of a pair of centrioles surrounded by a cloud or amorphous material
- undergo replication in preparation for mitosis
in prometaphase
- nuclear envelope breaks down
- chromosomes attach to spindle microtubules via a protein called a kinetochore
in metaphase
- chromosomes will align at the equator of the cell
- kinetochore microtubules attach to sister chromatics to opposite poles of the spindle
in anaphase
- chromatids synchronously separate forming two daughter chromosomes
- kinetochore microtubules get shorter while spindle pole moves apart
in telophase/cytokinesis
- daughter chromosomes arrive at poles of spindle
- chromosomes decondensce and a new nuclear envelope reassembles around each set
cytokinesis is when
the membranes separate
in G1 the number of chromosomes is
2n
in prophase the number of chromosomes is
2n
in cytokiesis the number of chromosomes
2n
what is neoplasia
new growth
aka tumour
neoplasm
abnormal mass of tissue
- uncoordinated and excessive growth
- continues beyond cessation of growth stimuli
what does benign mean
remains localized
what is maligment
moves and invades various tissue
the ending of “oma” is
often denotes a benign tumour
eg. lipoma , adeoma
what does suffix carcinoma mean
malignant tumour of epithelial cell
what does the suffix sarcoma mean
malignant tumour of mesofermal . mesenchymal origin
muscle, cartilage and bone
what are two key factors for tumour differenetiation
morphological and functional
what is the difference between well differentiated and poorly differentiated
well differentiated, very different looking
pleomorphism is
cells that vary in size and shape
why is age a risk factor in cancer
accumulations of somatic mutations that accompanies aging of cells
a decline in immune competence may also play a role
anaplasia is …
poorly differentiated
- pleomorphism
- abnormal nuclear morphology
- nuclei disproportionally large
- presence of a large numbers and abnormal mitoses
- loss of cell polarity
why is chronic inflammation a risk factor for cancer
tissue damage
cell proliferation must occur to repair damage
activated immune cells to produce reactive oxygen species that can damage DNA
inflammatory mediators produced can promote cell survival
in addition to anaplasia, malignant tumours will often show
-ischemic necrosis (lack of blood supply, grown so quickly with not enough blood)
- areas of hemorrhage
- local invasion
(lack a capsule)
- metastasis (migration to distant tissues via lymphatics or blood vessels)
what are some acquired conditions that increase the risk of cancer
chronic inflammatory disorders
precursor lesions
immunodeficiency states
why are precursor lesions a risk factor for cancer
localized morphologic changes in epithelial tissue that increase the risk of malignant transformation
(hyperplasia, metaplasia, dysplasia)
what is hyperplasia
increase in number of normal cells
what is metaplasia
replacement of one differentiated somatic cells with another
- occurs in response to chronic irritation so that cells can better withstand the stress
- occurs due to reprogramming of stem cells or undifferentiated mesenchymal cells found in connective tissues
what is dysplasia
presence of abnormal cells
why are immunodeficient patients at an increased risk for cancer
they have a higher than normal incidence of chronic infection from viruses
repeated rounds of cell replication creates a …… the higher likehood of accumulating mutations resulting in malignancy
fertile ground for development of malignant tumours
what are the three types od mutations
initiating
driver
passanger
what is an initiating mutation
found in all progeny, begins
the process towards malignant transformation
Essentially the first driver mutation
- Often include loss-of-function mutations in genes that maintain genomic integrity
* Leading to genomic instability
what is a driver mutation
mutation that increases
malignant potential of the cell
what is a passanger mutation
mutation with low malignant
effect
what are the classes of mutated genes in driver mutations
proto-oncogenes
tumour supressor genes
genes regulating apoptosis
genes responsible for DNA repair
what is a proto oncogene
- gain of function mutations => oncogenes
promote excessive cell growth
- created by mutations
- can include growth factors for their receptors, signal transducers, transcription factors or cell cycle components
what are tumour suppressor genes
- generally loss of
function mutations
are genes regualting apoptosis
can be gain or loss of
a function
what do genes responsible for DNA repair do?
- generally loss of
function
- affected cells aquire
mutations at an
accelerated rate
tumour progression once established, tumours evolve …… based on …….. of the fittest
genetically
survival/selection
mutations occur at random
Tumour subclones have to compete for
access to nutrients
best at accessing nutrients remain in tumour = more aggressive tumour
onco genes can turn on … without growth promoting signals
proliferation
Ras in oncogenes
- Downstream component of receptor tyrosine kinases
signaling pathways - tyrosine then activates Ras
- Ras activates MAP kinase
- Map kinase activates Mek
- Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors
- downstream signaler for lots of growth factors
- EGF, PDGF, and CSF-1
proto onco genes are …… but when mutated are named …
present in healthy cells
oncogenes
PI3K in oncogenes
- common in certain cancers
- promotes cell proliferation
- inhibits apoptosis
PI3K in healthy cell receives signal and activates and works downstream to activate Akt
(Akt activates cyclin A and D and decreases/ inactivates p21 and p27)
Myc in oncogenes
what is it?
what happens when Myc is induced and activated?
MYC is a transcription factor
- IMMEDIATE early response gene
INDUCED BY - Ras/MAPK
- stimulates transcription
of CDKs
WHEN ACTIVATED
- increases cell proliferation and growth
- increased telomerase activity
- May also allow more terminally differentiated cells to gain characteristics of stem cells
what is the warburg effect
glycolytic enzymes are up- regulated
chooses the lactate to pyruvate even though there is oxygen
Cdks and cyclins in oncogenes
- most important checkpoint is G1/S
- if you can get it going
rapidly, there is more
success
tumour suppressor genes apply …… to cell proligeration
the brakes
abnormalities in tumour supressor genes lead to …..
failure of growth inhibition
many such as RB and p53 recognize genotoxic stress resulting in
- shutting down proliferation
- Activation of oncogenes aren’t enough for cancer
induction, usually requires loss of tumour suppressor
genes as well
what is the enabler of genomic stablity
TP53
- cell cycle arrest and apoptosis in result of DNA damage
what are the two main inhibitors of cell cycle progression
Rb
(inhibitor of G1/S transition)
CDKN2A
(p16 negative regulator of cyclin dependant kinases)
hypophosphorylated RB
releases E2F
more G1s2 complex is synthesized in favourable conditions
what form do we usually find Rb in a quiescent cell
hypophosphorylated
(hugging of E2F)
ACTIVATED FORM
what form is RB in to facilitate passing through the G1/S checkpoint
hyperphosphorylated
what is direct loss of function of Rb
loss of function involving both RB alleles
what is the indirect loss of function of RB
- Gain of function mutation upregulating CDK4 /cyclin D
- Loss of function mutation of CKIs (p16)
TP52 codes for
is the actual gene that codes for : p53
- regulates cell progression, DNA repair, cellular senescence and apoptosis
Most frequently mutated gene in human cancer
p53 functions in the presence of
DNA damage
- stimulates DNA repair
if DNA is repaired -> cell cycle can resume
if DNA repair fails -> p53 will activate pro-apoptosis pathways
what does p53 induce
p21
- can shut down checkpoints in the cell cycle
is mdm2 is mutated what does it do
it hugs p53 and inhibits it
what is senescence in a cell
permanently exited the cell cycle and never divides again
With loss of p53,
DNA damage goes
unrepaired & driver
mutations
accumulate in
oncogenes & other
cancer genes —>
malignant
transformation
what would happen if there was a mutation of p16
Acquired mutations detected in many cancers
can also be silenced by hypermethylation rather than mutation
Inhibits Cdk4-
Cyclin D complex (G1-
cdk complex) needed for
progression through the cell
cycle
At least 1 of the 4 key regulators of the cell cycle is
dysregulated in the significant majority of all human cancers
what are the 4?
p16, cyclin D, Cdk4, RB
APC in tumour surpressor genes
- Very commonly
mutated in colorectal
cancers - Part of Wnt-B-catenin
pathway
E- cadherin in tumour supressor genes
Loss of function
mutations can
contribute to loss of
contact-inhibition in
tumours and
metastasis
All cancers display 8 fundamental changes in cell
physiology:
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Altered cellular metabolism
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- Ability to invade the host immune system
Warburg effect is when
Cancer cells take up high levels of glucose and
demonstrate increased conversion of glucose to lactate
- Even in the presence of ample oxygen
- Also called aerobic glycolysis
Why do you suppose a cancer cell is relying on glycolysis alone for ATP production?
Provides rapidly diving tumour cell with metabolic
intermediates needed for synthesis of cellular
components
T or F Cancer cells can evade senescence
T
- Likely due to loss of functions mutations in p53 and p16
- Allows cell to pass through G1/S checkpoint
normal cells divide ….. times and then become senescent
60-70
what are the componenets of the GI system
Alimentary canal
- esophagus
- stomach
- small intestine
- large intestine
accessory organs
- liver / galbladder
- pancreas
what is the alimentary canal
tubular like structure that makes direct contact with food
- has a typical set of histologic layers that surrond the lumen
composed of :
oral cavity
pharynx
esophagus
stomach
small intestine
(duodenum , jejunum and ileum)
large intestine
( cecum, appendix, ascending , transverse, descending, rectum)
what are the accessory organs
derived as outgrowths from alimentary canal
- not part of the straight tube
- function as glands and secrete substances into the canal
include
- salviary glands
- liver
- galbladder
what is the main function of alimentary canal
propulsion
moving food along the tube
what are the two secretions of the alimentary canal
hormonal
fluid or mucous
what are the two types of digestion
chemical
- enzymes and acid that break down the bonds in food
mechanical
movements of the canal to mix food and break it apart and increase the SA : volume of food
how is the absorbtion done in the alimentary canal
movement of lumen into blood stream
we ingest 1L of water a day, and 4-6 L of water into the canal
macro and micro nutrients
what is the immune function of the alimentary canal
- protection from ingested microbes that are harmful
- aiding microbes that are useful
- educating the immune system about weather something has been ingested is harmful or harmless
what are the layers of the alimentary canal
mucosa - epithelial lining , laminal propria , muscularis mucosa
submucosa
muscularis
serosa
where are neuroendocrine cells in the alimentary canal
interspersed among the epithelium and release signals in response to different nutrients or chemical conditions in the lumen
columnar with microvilli help in what? cubodial or squamous?
absorbtion and secretion
protection from abrasion
what is the purpose of goblet cells in the epithelial layer
mucous secretion
what is the lamina propria a site of?
- blood and lymphatic vessels
- immune tissue
what is the muscularis mucosa
used to alter the shape of the mucosa to optimize mixing and exposure of the epithelial cells to lumen contents
the submucosa is
a loose connective tissue with larger blood vessels and lymphatics
- larger glands
- large lymphatic nodules
- a plexus of neurons exist
what is meissners plexus
tends to regulate secretions and convey sensory info about whats in the lumen
muscularis layer is usually an …. and …. layer.
inner and outer
the inner layer of the muscularis is
the circular layer
- smooth muscle fibres concentrically surround the lumen
when it contracts, it squeezes the lumen shut
the outer layer of the muscularis is
the longitudinal layer
- smooth muscle fibres run along the length of the canal
what is auerbachs or myenteric plexus
- muscularis layer
- regulates the movements of these muscular layers
- found in between the two layers
the adventitia layer of the alimentary canal
in the esophagus
- connective tissue that anchors the esophagus in the chest cavity
the serosa layer of the alimentary canal
loose connective tissue that is covered by simple squamous mesothelium
- mesothelium secretes fluid that collects in the abdominal (peritoneal) cavity
- source of peritoneal fluid
- serosa is continuous with what is known as the visceral peritoneum
what is the peritoneal cavity
fluid filled gap between the wall of the abdomen and the organs that are contained within the abdomen
where is visceral formed
by the serosa and the capsule of the layer
what does the mesothelia secrete
fluid that collects in the abdominal (peritoneal) cavity
the parietal is the ….. of the abdominal wall and is …… to inflammation and other …
inner lining
extremely sensitive
chemical irritants
the only function of the esophagus is …..
propulsion of the food forward
peritoneal cavity is to …
host the organs
how long is the esophagus
25 cm long, located behind sternum
what is the esophagus divided into
upper and lower sphincter
what is the role of the upper sphincter
when it closes, it pushes the food from the pharynx to the esophagus
what is the role of the lower sphincter
limits movement of the stomach acid into the esophagus
relaxes to receive swallowed food
what type of cells does the esophagus have
stratified squamous, adventitia instead of serosa
what is the purpose of the stomach muscular movements
mechanical digestion and propulsion into the small intestine
what are the chemical digestion roles of the stomach
acid denatures proteins and kills ingested bacteria
secreted enzymes help to digest protein
tells when the stomach is full
(regulates food intake)
in the stomach what kind of cells are there
low columnar cells
parietal cells
- secretes acid and intrinsic factors (B12 absorbtion)
- other mucous secreting cells
muscularis
- oblique layer
what is a pyloric sphincter
regulates the amount of acidic chyme that enders the duodenum
the small intestine is the main
digestive organ
what is the small intestine the site of
- chemical digetion , absorbtion and secretion in the alimentary canal
- large surface area
what are the three seperate components of the small intestine
duodenum
- short C shaped tube that recieves chyme from the stomach and overlies the head of the pancreas
jejunum
- both the dudenum and jejunum have specialized immune tissue
ileum
- longest portion
- main function is reabsorbtion of bile, salts, water, micronutrients
the small intestine has ……. , ….. and ….. meant to optimize surface area
highly folded epithlium
mucosa(villi)
submucosal layers(circular folds)
small intestine consists of …. with many …. and is interspersed with ….. and cells that secrete chemical messages into the blood
columar epithelium
micorvilli
goblet cells
messangers in the small intestine can help regulate
propulsion, overall metabolic function , secretions from the pancreas and liver
the main function of the large intestine is
absorbtion of water , storage of stool , houses majority of microbes in the gut
- not really involved in nutrient absorbtion
what cells are the large intestine composed of
low columar cells with fewer microvilli
plenty of goblet cells
what is unique about the muscular layer of the large intestine
- continuous circular muscle layer
- longitudinal muscle layer is separated into bands that do not completely surround the canal but always have circular layer
why do we need the turns in the large intestine
slow down stool, accumulate stool , more mucous
the accessory organs dont contact …….. directly. they all have ….. that convey their secretions to the lumen of the ….
ingested substances
secretions , duodenum
what are the main roles of the liver
- carb metabolism
- protein synthesis
- lipid metabolism
- detox of molecules so that they can be secreted into bile and defecated
- making hydrophobic molecules water soluble so that they can be eliminated by the kidney
- storage of vitamins and minerals
- synthesis of bile
- endocrine secretion of IGF-1 (growth)
what are the main functions of gallbladder and pancreas
galbladder
- storage and modification of bile (release into dudenum)
pancreas
- exocrine, secretes digestive enzymes that are crucial for carb , protein and lipid chemical digestion
endocrine
- secretes hormones that impact glucose , protein and lipid metabolism into the blood stream
(insulin, gluagon, lipids)
increased bowel sounds (hyperactive) can be a indication of
diarrhea, gastoenteritis , IBS , laxitive use
early bowel obstruction
what are some indications of decreased (hypoactive) bowel sounds
emergent conditions
- bowel obstruction , peritonitis , intestinal ischemia
deep or visceral abdominal pain can come from
stretching, ischemia or chemical irritation of a component of the alimentary tract or accessory organ
guarding of the abdomen is
voluntary contraction of the abdominal musculature due to abdominal discomfort
- anxiety
- can be serious but more often less
what is rigidity of the abdomin
involentary contraction of the abdominal musculature , severe pain
bile (ruptured colecytitis) , infected material (rupture or ishemic intestinal wall), pancreatic secretions (pancreatitis) , gastric or duodenal contents (perforted peptic ulcer)
inflamed structure rubbing against the parietal peritoneum (appendicitis)
abdominal pain in the centre is a sign of
visceral pain from the alimentary tract or accessory organs
pain in the 6 side regions can be a sign of
irritation of the parietal peritoneum
non Gi organs
hepatomegaly pathology
normal soft to abnormally hard or firm liver
increased size of liver
irregular edge - heppatocellular carcinoma
liver cirrhosis is
large liver with firm , non tender edge
