MCM 2-13 Growth Control Flashcards
internal factors that regulate growth control
apoptosis, terminal differentiation, senescence
apoptosis
programmed cell death
occurs during normal development (formation of digits, etc.)
most cells require trophic factors to stay alive, in absense of these signals, cells initiate apoptotic pathway
- signaling cascade = activation of cystein proteases called caspaces from procaspase forms
- these digest important intracellular structural proteins like lamin and cytoskeletal proteins.
what happens to cells when they apoptose?
apoptotic cells shrink and fragment, releasing small, membrane bound apoptotic bodies that are phagocytized by macrophages.
-This controlled waste disposal prevents cytosolic contents from leaking into the EC space which would cause inflammation (this happens in necrotic cells)
terminal differentiation
process by which the specific gene upregulatory proteins of certain differentiated cells (neuron, cardiac muscle cells) prevent the cells from dividing further. Significant barrier to recovery from spinal and cardiac injuries.
Senescence
process by which cells of a given cell line stop dividing
due to absence of telomerase (an enzyme with an RNA portion used to add six-base repeats to telomeres)
-allows for complete syntehsis of the lagging strand in DNA replication
when telomeres get too short, p53 activated, leading to senescence. This limits unwanted proliferation and prevents replication of incomplete and unstable chromosomes.
Most adult tissues lake telomerase
external factors that regulate growth control
Growth factors, Cell ahdesion (Cell-EM interactions and Cell-cell interactions)
Growth factors
chemical messengers that influence cell growth. They are concentration and cell-type specific.
They can act locally (PDGF released by platelets to stimulate wound repair)
or systemically (erythropoetin produced by kidney to stimulate red blood cell differentiation in bone marrow)
Cell Adhesion
Cell-ECM interactions - anchorage dependant cell growth. ADhesion to the ECM stimulates cells to proliferate. Interactions via folal adhesions stimulate convergent pathways.
Cell-Cell Interactions - contact inhibition. Serve as negative regulator of cell proliferation (wound repair)
how do normal cellular genes become oncogenic?
normal cellular genes with potential to become oncogenic are called proto-oncogenes.
protooncogense have important normal cellular functions: stimulate cell growth and/or proliferation.
conversion to oncogene results in elevation/unregulated activity
a mutuation in even a single allele of proto-oncogene can cause abnormal growth/differentiation.
proto-oncogene mutations are ________ and of what types?
proto-oncogene mutations are somatic and of the following types
deletions or point mutations in the coding sequence - leads to production of hyperactive protein in normal amounts
gene amplification - leads to normal protein being overproduced
chromosome rearrangement - when gene is moved into the vicinity of a strong enhancer, normal protein is overproduced
when the gene is fused to an actively transcribed gene, a fusion protein is either produced in large amounts, or is simply hyperactive
how tumor suppressor genes regulate growth
TSG’s generally function to inhibit growth by opposing activity of proto-oncogenes.
both alleles of TSG must be lost before uncontrolled growth will occur (loss of heterozygosity)
cancer-predisposing genotypes related to tumor suppressor genes are inherited. - one can inherit a single bad tumor suppressor allele and be more likely to develop cancer due to a somatic loss of the other tumor suppressors alleles function.
why do most cancers involve cumulative mutations?
cells undergoing uncontrolled growth will form tumors.
once they obtain the ability to invade other tissues and metastasize, they form malignant tumors and have become cancer cells.
the transition between these two states typically occurs in steps, each marked by a new mutatiion in a different proto-oncogene or TSG.
because of this mutation profile that develops, oncotherapies are best tailored to the individual
3 types of factors that regulate growth control
- cell lineage (internal)
- external/diffusable factors (growth hormones)
- cell/cell and cell/ECM adhesion interactions
describe cell lineage control of cell growth
internal control of G1/S transition
apoptosis - carefully controlled waste disposal
also occurs in normal development (digitization and neuronal connection trimming)
- occurs in normal adult cells (lining of gut, mammary tissue post lactation)
- also occurs as a result of checkpoint error during DNA replication cycle
improper apoptosis during digitization
syndactyly
what causes neuronal cell apoptosis
during development, absense of trophic factors (survival factors) excreted by target cells
cell death balances the number of neurons to number of target cells
describe apoptotic cells
cells shrink, form membrane blebs that fragment, releasing small membrane bound apoptotic bodies that are phagocytized by macrophages
-prevents inflammation
as opposed to necrotic cells that swell, burst, and cause huge inflammation
describe a neuron that is receiving enough trophic factors vs one that is not
receving enough trophic factors - initiates signaling cascade that causes pro-apoptotic factor BAD to get sequestered in cytosol. cell survives.
not receiving enough - BAD remains active, interacts with anti-apoptotic proteins in mitochondria.
End result = inhibitory role on BAD is lost, ions enter mitochondria. cytochrome c released. this gives rise to a catalytic cascade, which causes the internal degredation and apoptotic bodies start to form and get released.
Terminal Differentiation
Second internal mechaism of G1/S transition control
some cells stop dividing (express a novel set of genes for the specialized function of cell)
ex) neurons and cardiac muscle cells
causes barrier to spine injury and heart disease treatments
Senescence
Third mechanism of internal control of G1/S transition
cells in culture will stop dividing after 50-100 divisions due to absence of enzyme called telomerase
this causes the telomeres to shorter with each round of replication, signaling pathways (including p53 upregulated which upregulates p21 CDK inhibitor, blocks cells in G1
important for limiting unwanted differentiation
telomerase
an enzyme, more specifically a ribozyme (half protein, half RNA)
-adds 6 base pair noncoding repeats to ends of chromosomes (parental)
allows for more complete syntehsis
most ______ cells lack telomerase
somatic cells
growth factors
a type of external factor influencing cell cycle movement
-some act locally (PDGF) some act distantly (erythropoietin)
Cell-ECM interactions
a type of external factor influencing differentiation/cell cycle/growth
“anchorage dependent cell growth” e.g. control of cell proliferation/differentation at the skin epidermis
healthy cells that are suspended will not proliferate, must be given patch to adhere to.
cells allowed to adhere to small amounts of ECM protein (fibronectin, collagen) will form a few focal adhesions and some will proliferate
Cell adhesion to ECM can induce proliferation
cell-cell interactions
cell density dependant growth inhibition = contact inhibition (important in wound repair)
cell adhesion to ECM, not just structural but can also control
cell fate
describe skin epidermis example
skin epidermis is hostile, constantly sloughing off
only cells in contact with basal lamina can undergo cell division - they are experiencing anchorage-dependent cell growth/differentiation
when these cells escape, integrins get downregulated, and will start differentiating into skin cells and upregulate adherins and IF to form cell:cell desmosomes that are important for the barrier function of skin
process goes awry - tumors
growth control is a balance between
stimulatory and inhibitory signals (kinase vs phosphatases) (GEFs vs GAPS)
example is MAP kinase pathway - cascade of various kinase signaling molecules activate downstream kinases that activate downstream molecules
when kinases activate they are a phosphorylated intermediate
phosphatases can dephosphorylate, causing deactivation
RAS is activtated by GEF, inhibited by GAS. balance of GEF and GAS determines if pathway is activated
characteristics that cancer cells may or may not exhibit
do not senesce (active telomerase or inactive p53)
lack growth factor dependence
lack anchorage dependence (will grow in suspension )
no-cell:cell contact inhibition (cells will pile up on top of each other and form Foci)
most cancers result from
mutations affecting the function of proteins involved in important regulatory signal transduction pathways
2 main classes - oncogenes and tumor supressor genes
Oncogenes
example?
mutated/overexpress versions of genes normally found in cellular genomes (proto-oncogenes)
HER2 and HER2B
Generally the result of somatic mutation (not inherited - would cause inviable fetus)
-they normally stimulate growth/cell proliferation, their mutation causes elevated or unregulated activity
mutation of single allele is enough to cause abnormal growth
what causes the HER2 mutation?
upregulation of expression of cell surface receptor
tumor supressor genes
normally found in genomes to oppose activity of proto-oncogenes
Retinoblastoma and P53
both alleles must be mutated, those who inherit iare more susecptible due to only needing a single mutation.
ex) (BRCA1/BRCA2)
mutations in tumor supressors makes them an inactive form
Retinoblastoma
tumor suppressor cell
-the active Rb sequesters transcription factors like eFII.
Phosphorylation by CDK causes the release of TF factors and transcription of the target gene (permits G1-> S transition)
loss of retinoblastoma function - unregulated transcription
p53 can upregulate p21, which inhibits CDK which can no longer phosphorylate Rb to release the Transcription factors
p53
Tumor supressor, prevents damaged DNA from being replicated.
-normally upregulates p21 which blocks the G1 CDK, which prevents Rb from getting phosphorylated, keeps TF locked down
Mutated/damaged p53 = damaged DNA gets replicated.
increases possibility that new mutations will be “Seen” in progeny
damaged DNA can be replicated - chromosomes lacking telomerase can then fuse/fragment causing gene duplication or loss
p53 mutations are common in cancer
50% of all
75% colorectal
How do DNA viruses cause cancer?
DNA viruses carry genes the encode proteins to block Rb andp53 function, leading to hyperproliferation and transformation of infected cells = turn on cell transcription machinery to assist in replication
SV40 Virus
encodes large T antigen which binds Rb and p53, blocking their function
HPV
produces two proteins (e6 and e7) which bind p53 and Rb, respectively.
stages in cancer progression
- loss of cell division/growth control leads to a tumor
- mutations within the tumor that eventually allow cells to break off and metastasize form widespread malignant tumors leading to cancer
transition occurs in multiple stages, each marked by a new mutation in a different oncogene or tumor suppressor gene
each tumor has a unique
genetic profile, allowing for tailored treatment options
the kinase that phosphorylates the Rb protein, allowing E2F dependent transcription can best be described as a
proto-oncogene
