tumor suppressors Flashcards
unlike oncogenes, tumor suppressors
have to be turned “down” or “off” to contribute to cancer spread
the tumor suppressor genes and their resulting proteins usually
prevent tumorigenesis
tumor suppressor genes
are actual genes
tumor supressor proteins
are the resulting proteins
tumor suppressor genes usually follow
“two-hit hypothesis”
_____ copies of tumor suppressor genes usually
both copies of the genes usually have to be faulty for cancers to develop, recessivee?
BRCA is a
tumor suppressor gene
mutation to BRCA is said to be passed down
in a dominant fashion
why is BRCA mutations passed down in a dominant fashion
one copy is already “out”, people are a single mutation away from developing cancer
how can tumor suppressor genes be turned down or off
chromosomal translocation, error with regulation, chromosomal deletion
chromosomal translocation (tumor suppressors)
moves the gene to a different part of the chromosome where it’s experienced less
error with regulation (tumor suppressor)
activator protein is deformed and never turns gene “on” or operator/promoter sequence is mutated
how can tumor suppressor proteins be turned “down” or “off”
hypomorphic or amorphic mutation
error with on/off switch
hypomorphic or amorphic mutation ( tumor suppressor proteins)
causes damaged proteins
error with on/off switch (tumor suppressor genes)
kinase, phosphatase or other “on/off” switch fails to turn protein on
examples’ tumor suppressors
p53
Rb
VHL
what gene codes for p53
TP53
where is TP53 located
on chromosome 11
what is p53 known as
the guardian of the genome
what is the primary job of p53
halt the cell cycle if DNA damage is detected
begin apoptosis cascade if the DNA damage is not fixed
what is the Knudson Hypothesis
the idea that cancer comes from a gradual accrual of mutations in various oncogenes and tumor suppressor genes
so basically the knudson hypothesis is saying…
we need to activate all 6 hallmarks
with p53 preventing DNA damage (mutations) then»»>
we shouldn’t ever satisfy the Knudson Hypothesis
p53 is best regulated by what
another protein called mdm2
what does mdm2 do
indirectly activates p53
in response to DNA damage, mdm2 will
unbind from p53, setting it free
p53 serves as an ____ for many
serves as an activator for many genes
what genes does p53 serve as an activator for
p21
BAX
BBC3
what does p21 do
halts the cell cycle
BAX function
cause apoptosis if BCL-2 does not block it
BBC3 function
codes for BCL-2 binding complex 3,
BCL-2 binding complex 3 function
blocks BCL-2 and helps cause apoptosis
who’s paradox?????
PETO’s :O
what is Peto’s Paradox
if an organism has more cells, its chances of getting cancer should be higher
elephants have more cells than us, why do they hardly ever get cancer
they have 40 copies of the TP53 gene, humans have 2
why have humans not evolved to have extra copies of p53
Rats w/ artificially high amounts of p53 tend to exhibit senescence faster than those with normal amounts
senescence
aging
what hallmark would the p53 pathway be
evading growth suppressors
resisting cell death
Rb gene codes for
Rb protein
Rb protein is a
pocket protein
pocket protein
has a pocket where another protein can bind perfectly
Rb sends a signal to
to stop the cell cycle between the G1 phase and the S phase UNLESS
b perpetually sends a signal to stop the cell cycle between the G1 phase and the S phase unless what???
its pocket has been filled with a specific molecule not normally present in the cell
G1 and S
G1 is organelles duplicated
S is chromosomes duplicated
a cell may only progress to the next phase of mitosis if
Rb stops sending its signal
in cancer, Rb is
often faulty and fails to deliver its signal
when Rb dosen’t work properly
cells may progress from G1 to S phase whenever they want
which hallmark is the Rb pathway
Evading growth suppressors
VHL stands for
von Hippel-Lindau protein
VHL acts as an
E3 ubiquitin ligase
what does an E3 ubiquitin ligase do
attaches ubiquitin molecules to proteins, signaling that they need to be destroyed
what does VHL do????
ubiquitinates the HIF protein family
does HIF stand foe
hypoxia inducible factor
HIF proteins are
activators for many different genes that are all linked to angiogenesis
angiogenesis
the formation of blood vessels
In cancer, VHL is
absent, and HIF is constantly present
if HIF is constantly present
it allows cancerous tumors to grow new blood vessels as needed
what hallmark is the VHL pathway
inducing angiogenesis
neoplasia
any new growth, often synonymous with a tumor
tumors are classified based on
the type of cell that becomes cancerous
the two big categories of cancer classification
sarcoma carcinoma
suffix for cancer
oma
cancer prefix
make quizlet
how many specialized cell types in the body
2990
all specialized cells are derived from
the zygote formed when a mother’s egg meets a father’s sperm
cell differentiation
a cell growing up and deciding what it wants to be
cell differentiation is usually
irreversible
what is the self-renewal of a stem cell
one cell grows up, the other remains a stem cell
what are stem cells
cells that undergo self renewal
types of stem cells
totipotent stem cells
pluripotent stem cells
totipotent stem cells
can grow up to become anything
totipotent stem cells only truly exist…
in zygotes/ very early in development
pluripotent stem cells
can grow up to become several things, but not all things
there are many pluripotent stem cells…..
in a full-grown body
progenitor cells
they are no longer stem cell
do progenitor cells self-renew
no, although some still divide, they can still become many different things when they grow up
differentiated cells
cells that are all grown up
rule of thumb for cancer and stem cells
the more grown up a cancer cell is, the less severe the cancer will be
embryonic stem cells can spit to become a cell in what 3 categories
mesoderm
endoderm
ectoderm
another name for sarcomas
sarcomata
sarcomas are
very rare types of cancer
about how many new cases of sarcomas in the US every year
15k
sarcomas affect..
cells of mesodermal origin
example of cells of mesodermal origin that sarcomas affect
fat, muscle, cartilage, lymph and bone cellls
where is blood created
inside of bone
blood cancers are considered
“sub-types” of sarcoma
examples of blood cancers that are subtypes of sarcomas
leukemia, lymphoma, myeloma
sarcomas are nearly
nearly always malignant , can often happen in people under age 50
in a stromal cell sarcoma
tumor begins forming in the middle of a busy structure, as opposed to the edge
what is a carcinoma
a type of cancer that affects cells of endothermal or ectothermal origin
most carcinomas end uo affcecting
epithelia
carcinomas are much more
much more common than sarcomas
can carcinomas sometimes be benign
yes, although they are often not
carcinomas occur mostly in who
people above the age of 50
function of epithelial tissues
surround all organs and serve as a coating
epithelia cells regenerate
from bottom to top and cells quickly “grow up” as they reach the surface
epithelial tissues come in
many shapes and sizes
looking at a picture of a carcinoma
cells don’t mature and flatten out as they reach the surface
when carcinomas are small and limited to the epithelial layer
they are cancer in-situ
origin of carcinomas and sarcomas
carcinomas: epithelium
sarcomas: connective tissues
both carcinomas and sarcomas are
malignant
frequency of carcinomas and sarcomas
carcinoma: common
sarcoma: rare
preferred route of metastasis carcinoma, sarcoma
carcinoma: lymph
sarcoma: blood
Are carcinomas in the in situ phase
yes
are sarcomas in the in situ phase
no
stage 0
Very early cancer mass contained entirely within its tissue. Also called “cancer in situ”
stage 1
Cancer contained within one area, often can be surgically removed
stage 2
Cancer “early locally advanced”. It has begun spreading to nearby lymph nodes.
stage 3
Cancer “late locally advanced”. It has spread more to the nearby area.
the difference between types 2 and 3
depends on the cancer type
stage 4
cancer has metastasize to other organs or parts of the body
many cancers are also staged using the
TNM
TNM
tumor, node, metastasis system
sample TNM notation
T3N1Mx
T in TNM
stands for the size of the tissue and how many foreign tissues it has invaded
T number varies from what in TNM
0 (smallest) to 4 (biggest)
if the size of a tumor is unknown or can’t be determined (TNM)
Tx
the classification of T changes
the type of cancer and which tissues surround the area
N in TNM
stands for the extent of the spread to the lymph nodes
codes for N in TNM
x-can’t tell
0-none
1-in very local lymph nodes
2/3-in far away lymph nodes
what is the lymph system
a series of lymph vessels and lymph nodes
the lymph system does what
serves as a place to store and filter interstitial fluids
The nymph nodes are more _____ than _____
loose, than blood vessels
it is much easier for cancer cells to
enter lymph nodes than blood vessels
M in TNM
stands for metastasis
numbers of M in TNM
M1
M0
Mx
M1
if there is metastasis in other organs
M0
if there is not metastasis in other organs
Mx
if you cannot tell if there is metastasis or not
what are the common cancer treatment
radiation
surgery
chemotherapy
radiation
using waves of radiation focused on the tumor
radiation is like
burning things with a magnifying glass
surgery
physically cutting out the tumor and surrounding tissue
chemotherapy
medication that stop mitosis of cells, generally affects all cells of body
pros of radiation
- safety for patient
- kills large proportion of cancer cells
- can relieve mass effect by shrinking tumor
- preserves organ
why does radiation have safety for the patient
only targets a very small area
what is mass effect
tumor pushes on surrounding tissue
cons to radiation
- damages surrounding tissue
- misses hidden metastases
- inconvenient (many doses for many months)
- increase the healing time in surgeries
pros to surgery
- can decrease mass effect
- can completely cure patient if whole tumor is removed
- convenient: (1 day surgery))
- ability to biopsy and test tissue
cons to surgery
- tough to kill microscopic disease
- does not target metastases
- risk of secondary infection
- patients must be able to tolerate anesthesia
- loss of a part or all of an organ
why is it tough to kill microscopic disease using surgery
one leftover cell can cause regeneration
pros of chemotherapy
- can kill cells in the entire body
- preserves organ
- patient-specific tailored treatment
can chemo kill metastases
yes
cons to chemotherapy
- usually can’t kill cancer alone
- inconvenient
- kills cells in random distribution
- systemic toxicity
chemo must be
coupled with radiation or surgery
why is chemo inconvenient
many doses over long time
why does chemo have systemic toxicity
affects all cells
what are the six hall marks
- proliferative signaling
- evading growth suppressors
- resisting cell death
- enabling replicative immortality
- inducing angiogenisis
- activating angiogenesis
to be cancerous must undergo…
some genetic changes that it to show each of the hallmarks of cancer
the genetic changes that cause cancer that occur on or around genes are sorted into what 2 categories
oncogenes and tumor suppressor genes
oncogene
gene that has the power to cause cancer when turned “on” or “up”
oncoprotein
the protein coded for by an oncogene
oncogenes and oncoproteins usually
don’t cause cancer, only do when there is some kind of mutation
before they mutate, oncogenes are called
proto-oncogenes
how can proto-oncogenes be activated
gene duplication , error with regulatory protein, error with regulatory DNA , chromosomal translocation
gene duplication (proto-onco)
the gene is accidentally copied, resulting in more expression of the protein
result of gene duplication (proto-onco)
genes have an extra copy and will expressed at higher rates
error with regulatory protein (proto-onco)
the protein that would turn a gene off can no longer do so
(thinking of regulation) almost all genes have
promoters and operator just upstream of the gene
upstream
in front
example of a promoter
where RNA polymerase binds to turn DNA into mRNA
example of an operator
where regulatory proteins bind to alter expression of the gene
activators
turn expression up
repressor
turn expression down
so with an error with regulatory protein…. there is a
repressor that does not work
error with regulatory DNA (prot-onco)
the DNA in the operato mutates so that regulatory proteins cannot bind there anymore
chromosomal translocation (proto-onco)
the gene “moves” during DNA replication and has a new operator
things that causes the activation of oncoproteins
hypermorphic mutation
failure of on/off switch
failure of ubiquitination
hypermorphic mutation (proto-onco)
mutation in protein structure makes it work faster
failure of on/off switch
kinase, phosphatase, or other on/ off switch fails to turn off oncoprotein
failure of ubiquitination
failure to destroy a protein leads to higher levels of them
examples of oncogenes
RAS
BCL-2
Telomerase
ubiquitination is the
systematic and selective destruction of a protein
RAS genes have over
150 products
the most common RAS genes are
H-ras, N-ras, K-ras
H-ras is found on
chromosome 11
N-ras is found on
chromosome 1
K-ras is found on
chromosome 12
each one of the RAS genes is responsible for
turning on or off various proteins that turn on proteins,
RAS genes are one of first steps starts a cascade
that will ultimately turn on genes that often lead to more cell division
RAS proteins themslves can be
turned on of off
mutant RAS is found in
30% of cancer, 90% of pancreatic cancers
each RAS protein can be turned “on” or “off” by a system v
very similar to phosphorylation
in the case of RAS proteins being turned on or off, RAS proteins will either be bound to
GDP
GTP
GDP
guanidine diphosphate
when RAS proteins binds to GDP
it will be off
GTP
guanidine triphosphate
when RAS proteins binds to GTP
it will be on
RAS proteins are almost always located
very close to a receptor protein on a cell’s membrane
when a receptor protein on the cell membrane is activated by RAS
a cascade will cause a GDP to be removed from RAS and a GTP to be added to it, causing RAS to become active
when other things happen, RAS is turned off by having
the third phosphate group cut off ( becomes GDP)
while all 150 RAS proteins are somewhat different
the begininng amino acid sequences are the same
Almost all mutations affecting the ____codon of any RAS protein have
affecting the 61st codon, have been shown to inhibit the conversion of GTP to GDP
mutations to RAS proteins inhibiting the conversion of GTP to GPD causes
the RAS proteins to be always on and cells are always told to grow `
RAS would be an example of which of the 6 hallmarks
proliferative signalling
BCL-2 is
a protein involved in the apoptosis pathway
BCl-2 usually works to
PREVNT apoptosis
in some cases, BCL-2
is turned up too high, which stops p53 and its friends form initiating apoptosis
when BCL-2 stops p53 and friends from iniitiating apoptosis
allows cancerous cells to proliferate
shutting off the overexpression of BCL-2 is crucial to
helping anti-cancer medications work, so we can let to body cure itself by committing apoptosis instead f killing it ourselves
genasense
an antisense drug
genasense is
perfectly complementary to mRNA strand that carries instructions to produce BCL-2
soooo genasense can
stop ribosomes from reading the mRNA and making the protein
which hallmark is the BCL-2 . protein
Resisting cell death
Every chromomsome has a
'’cap’’ on both end of the same 6 bases
every chromomsome has a “cap” on both ends of which of the same bases
TTAGGG
TTAGGG are repeated how many times
2500 times per chromosome in new cells
each time a chromosome replicates and the cell divides
part of the telomere is lost and the chromosome shortens
after the telomere is entirely lost…..
chromosome replication and cells division stops completely
Hayflick limit was by
Leonard Hayflick in the 1960s
what did Hayflick discover
that human cells are only capable of replicating a certain number of times
human cells can only replicate about how many times
50-70
telomerase is an enzyme
that lengthens the telomeres
telomerase is almost
almost always off in somatic human cells,
exception of a new cell types where telomerase is off
stem cells, white blood cells, sperm cells, skin cells, etc
does every cell have the gene to make telomerase
yes
why is telomerase considered an oncoprotein
because without it, cancer cells would have a limited number of replications because they couldn’t replicate anymore
what hallmark is the telomerase pathway
enabling replicative immortality
