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11111 Cell Proliferation
UC MED 2015
120
Medical
Graduate
11/03/2011

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Term
What must occur to lead to a complete loss of growth control?
Definition
A series of mutations
Term
If a mutation is inherited, the risk of developing the malignancy is?
Definition
increased
Term
Carcinomas happen in?
Definition
epithelial cells- environmental damages are likely the cause
Term
Sarcomas happen in?
Definition
supporting tissues of the body
Term
Cancer of the lung, stomach, skin and colon are?
Definition
carcinomas
Term
Cancer of the bone, blood vessels, and muscle are?
Definition
Sarcomas-such as osteosarcoma or rhabdomyosarcoma
Term
Cancer of the stem cells or bone marrow are?
Definition
Leukemias- such a lymphomas
Term
What is the problem with tumors?
Definition
Cell growing rapidly, not performing differentiated functions and they impinge on other tissues.
Term
What are two common treatments of tumors?
Definition
1) Remove(surgery)
2) chemotherapy- most interfere with DNA synthesis...however they destroy normal cells as well resulting in hair loss, digestive problems(any normal cells with rapid turnover are affected the most)
Term
What life period is skipped by tumors when compared to normal cells?
Definition
senescence- after so many cell cycles most of the tissues die and then a few survivors regrow, tumors skip this stage altogether
Term
What type of cells need more serum normal or trnasformed?
Definition
Normal, they need 10%; transformed need <1%
Term
What is the difference between normal and transformed cells in the expression of LETS(fibronectin)?
Definition
Normal-High
Transformed- Low
Term
What is the difference between normal and transformed cells in agglutinated lectins?
Definition
Normal- No
Transformed- Yes
Term
What is the difference between normal and transformed cells when comparing forms of carbohydrates on the cell surface?
Definition
Normal- normal
Transformed- Fetal forms
Term
What is the difference between normal and transformed cells in enzyme expression?
Definition
Normal- adult
Transformed- fetal isozyme
Term
What type of cell will grow on top of each other?
Definition
Transformed

Normal-want to communicate and will grow in one layer in a petri in a cobblestone appearance
Term
What are some of the differences seen in transformed cells(5)?
Definition
1) Go is ignored as the cells cycle
2) G1 transit time is reduced when compared to non-transformed cells
3) Cells form multilayers; cell death via lack of nutrients
4) Reduced serum requirements for growth
5) Cell shape altered, cells less adherent to substrata, more rounded (reduced anchorage dependence)
Term
What does the serum provide?
Definition
Growth factors that tell the cells to proliferate, so transformed cells don't need factors to tell them to grow.
Term
A cell's response to a growth factor is determined by? Give me some examples of this...
Definition
It is determined by whether the cell expresses the receptor for that growth factor

Examples...
1) response to glucagon
a-muscle-no receptors=no response
b-liver-contains receptor= response
2) Response to Insulin
a-muscle-contains receptor= response
b-liver-contains receptor= response
Term
Tell me more about growth factors...
Definition
1) small proteins that stimulate a cell to grow and differentiate
2) can replace serum in order for cells to grow
3) stimulates a cell through a series of events known as SIGNAL TRANSDUCTION
4) Very important in development and differentiation
5) Molecular weight can range from 6,000 to 32,000
Term
EGF
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Epidermal growth factor
2) 6045
3) 2-5 ng/ml
4) Fibroblasts, Glial cells, Hepatocytes, and SMC(smooth muscle cells)
Term
PDGF
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Platelet-derived growth factor
2) 32,000
3) 2-5 ng/ml
4) Fibroblasts, Glial cells, SMC
Term
FGF
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Fibroblast growth factor
2) 15,000
3) 10-15 pg/ml
4) Fibroblasts, Endothelial cells, Neuronal precursors
Term
NGF
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Nerve growth factor
2) 26,000
3) 5-10 ng/ml
4) Nuerons
Term
TGF-a(alpha)
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Transforming growth factor-a(alpha)
2) 6-10,000
3) 2-5 ng/ml
4) Fibroblasts, Glial cells, SMC, Hepatocytes
Term
TGF-ß
1) What does it stand for?
2) What is its molecular weight?
3) What is its active concentration?
4) What are its target cells?
Definition
1) Transforming Growth Factor-ß
2) 25,000
3) 1-5 ng/ml
4) Everything
Term
Pertaining to hormones and the glands that make and secrete them into the bloodstream through which they travel to affect distant organs.
Definition
Endocrine
Term
Of or relating to a hormone or to a secretion released by (endocrine) cells into the adjacent cells or surrounding tissue rather than into the bloodstream.
Definition
Paracrine
Term
Of, relating to, or being a substance that acts on surface receptors of the same cell that produced it.
Definition
Autocrine
Term
All of the growth factor receptors except TGF-ß have this type of domain?
Definition
Tyrosine Kinase Domain
Term
TGF-ß has this type of Domain?
Definition
Serine-Theronine Domain
Term
What is necessary for signal transduction?
Definition
Kinase activity
Term
All of the information for growth stimulation resides in?
Definition
It is in the receptor, not the growth factor
Term
What are some of the early responses to growth factors?
Definition
1) Turnover of PI
2) Increase in levels of intracellular Ca
3) Activation of Protein Kinase C
4) Formation of receptor-substrate complexes due to tyrosine phosphorylation
5) Activation of gene transcription
Term
What stimulates Protein Kinase C?
Definition
DAG
Term
What stimulates free calcium release from bound stores in the ER?
Definition
IP3
Term
Where can you find PI?
Definition
inner membrane leaflet
Term
What does lithium do?
Definition
It block inositol and CDP-DG from forming PI.
Term
What brings Ca from the outside?
Definition
IP4
Term
What brings Ca from the ER?
Definition
IP3
Term
Why do multiple growth factor receptors cluster together?
Definition
For autophosphorylation
Term
IP3 generated by?
Definition
Pl-C signal
Term
IP4 generated by?
Definition
PI-3' kinase
Term
Do all GF's need to increase intracellular free calcium levels?
Definition
No, for instane FGF doesn't.
But, PDGF and EGF do.
Term
What does an antibody to PIP2 do?
Definition
-Blocks hydrolysis and formation of IP3
-Blocks PDGF and EGF mitogenesis
-No effect on FGF-induced mitogenesis
Term
What two types of compounds are required to generate animal tumors?
Definition
1) initiators
2) Promoters
Term
What do tumor promoters activate?
Definition
Protein Kinase C (large lipleic proteins that don't turnover frequently
Term
What are the three classification of growth factors?
Definition
1) early
2) intermediate
3) late
Term
What is phosphorylated on tyrosine, threonine, and serine residues?
Definition
MAP kinases
Term
What enzyme can phosphorylate all of the residues for the MAPK to be activated?
Definition
MAP Kinases Kinase (also called MEK, for MAPK/ERK kinase)
Term
What activates MAP Kinase Kinase?
Definition
Phosphorylation by MAP Kinase Kinase Kinase (MAPKKK)
Term
What is an example of a MAPKKK?
Definition
raf
Term
In order for raf to be fully activated it requires?
Definition
ras to be active
Term
What is a GTP binding protein that is similar to the alpha subunit of G proteins?
Definition
ras
Term
What does raf do?
Definition
It will bind GTP and interact with phosphorylated raf to fully activate it by translocating to the membrane

Side note-while it is similar to the alpha subunit of G proteins, it does not activate adenylate cyclase
Term
How is ras activated?
Definition
Either tyrosine kinase receptors or by G-protein linked receptors
Term
What does GRB2 stand for and what does it do?
Definition
-Growth factor receptor binding protein 2
-binds to growth factor receptors and acts as a bridge for SOS binding; GRB2 binds to phosphotyrosine residues through SH2 domains
Term
What does SOS do? What does it do?
Definition
-Guanine nucleotide exchange factor
-SOS binds to GRB2, it is active and facilitates the exchange of GTP for GDP on ras
Term
What does GAP stand for? What does it do?
Definition
-GTPase activating protein
-It antagonizes SOS activity
Term
Which Cyclin is active during G1?
Definition
Cyclin D
Term
Which cyclin(s) are active during S phase?
Definition
Cyclin E and Cyclin A
Term
What is active during G2, which leads to M?
Definition
Cyclin B
Term
What is a serine/threonine kinase, which phosphorylates nuclear proteins and allows cell division to occur?
Definition
p34cdc2 and cdk1
Term
What forms a complex with p34cdc2 (it is synthesized in a cyclical pattern during the cell cycle)?
Definition
CyclinB
Term
What is a kinase which phosphorylates and inactivates p34cdc2?
Definition
wee1
Term
What also phosphorylates and inactivates p34cdc2 at an activity site?
Definition
CAK (CDK-activating kinase)
Term
What is a phosphatase which dephosphorylates p34cdc2 at two sites and activates its kinase activity?
Definition
p80cdc25
Term
When this happens, what do we call this...
-Cells swell
-Mitochondria dilate
-Organelles dissolve
-Plasma Membrane ruptures, releasing cytoplasmic material
-Inflammatory response frequently results
Definition
Necrosis
Term
When this happens, what do we call this...
-Cell shrinks
-Chromatin condenses
-Nucleus fragments
-Cell breaks into membrane enclosed vesicles
-Phagocytosis results (PS a marker)
-No inflammatory response
Definition
Apoptosis-regulated cell death
Term
If a mutation leads to an inability to undergo apoptosis, what happens?
Definition
Cells with damaged DNA can proliferate, increasing the rate of mutation, and the probability of developing a neoplastic cell.
Term
What are the three phases of apoptosis?
Definition
1) Initiation phase
2) signal integration phase
3) Execution phase
Term
What happens in the Initiation phase?
Definition
-Death receptors(tumor necrosis factor receptor)
-Deprivation of growth factors(lack of positive signaling blocks anti-apoptotic factors from working)
-DNA damage
-Mitochondrial integrity (oxygen deprivation, radiation)
Term
What protein family consists of both pro-apoptotic and anti-apoptotic factors?
Definition
Bcl-2
Term
When apoptosis is initiated, it is due to these proteases called?
Definition
caspases
Term
What leads to the activation of CAD, caspase-activated DNAse, destroying kinases and lamins)?
Definition
Execution caspases-they carry out most of the work leading to cell death
Term
What are the two ways to bring about apoptosis?
Definition
Activate death receptor or compromise mitochondrial integrity
Term
What do death signals include?
Definition
1 )growth factor withdrawal
2) Cell injury
3) Steroids
4) High cytoplasmic Ca2+
Term
Apaf stands for?
Definition
Pro-apoptotic protease activating factor
Term
Bcl-2, Bcl-x, and Bcl-w are examples of?
Definition
-Anti-apoptotic factors
-They can insert in outer mitochondrial membrane and antagonize channel forming pro-apoptotic factors
-Can bind cytoplasmic apaf and prevent it from forming the apoptosome
Term
What is Bax?
Definition
It is a pro-apoptotic factor, that does ion channel forming. It allows cytochrome C to leave the mitochondria more easily.
Term
What is Bid and what does it do?
Definition
It is a pro-apoptotic factor (BH3 domain only), it can bind to channel formers, but cannot form channel on its own.
Term
What is similar to anti-apoptotic factors, but cannot bind to apaf? It will dimerize with BH3-only pro-apoptotic factors in outer mitochondrial membrane to form an ion channel which promotes cytochrome c release.
Definition
Bax (channel forming)
Term
What when activated, dimerize with channel forming factors also binds to anti-apoptotic factors to block their binding with apaf, so the apoptosome can form?
Definition
BH3-only factors
Term
What is the protein required for forming structural core of the (retro)virus?
Definition
gag
Term
What is the envelope glycoprotein found in the membrane of the retorvirus?
Definition
env
Term
What is the reverse transcriptase, to convert RNA genome into dsDNA copy, which integrates randomly into the host chromosome?
Definition
pol
Term
What is the receptor for the colony stimulating factor-1?
Definition
v-fms
Term
What are the receptors for members of the FGF family?
Definition
v-bek abd v-flg
Term
What is a receptor for the stem cell factor?
Definition
v-kit
Term
What is a receptor for hepatocyte growth factor?
Definition
v-met
Term
What is a receptor for thrombopoeitin?
Definition
v-mpl
Term
What is jun?
Definition
transcription factor activated by MAP kinase
Term
What is the Insulin signaling pathways?
Definition
1) phosphorylate...IRS-1
2) form GRB2:IRS-1complex
3) form SOS:GRB2:IRS-1 complex
4) activates Ras-GDP to Ras-GTP
5) activates raf kinase
6) eventually activates MAP kinase(ERK) and ISPK(Insulin stimulated protein kinase)
Term
What protein also phosphorylates p34cdc2 at an inactivation site?
Definition
MYT1
Term
What is a caspase?

Where does it cleave?
Definition
Cysteine protease (catalytic triad with a cysteine at the active site)

It cleaves next to aspartate residues in target proteins
Term
What does FADD stand for?
Definition
Fas associated death domain protein (fas is membrane-bound ligand which binds to death domain receptors)
Term
How do growth factors block apoptosis?
Definition
1) PDGF- binds to receptor and activates PI-3 kinase
2) PI-3 kinase activation leads to the phosphorylation and activation of PKB(AKT) via PDK-1
3) AKT phosphorylates and inactivates BAD (BH-3 only pro-apoptotic factor)
4) MAP kinase kinase phosphorylates the protein kinase RSK, and activates it
5) RSK also phosphorylates BAD, to inactivate it
Term
What is BAD?
Definition
BH-3 only pro-apoptotic factor protein
Term
What happens when you have a mutated Bcl-2?
Definition
Over-expression tips balance to anti-apoptosis, and mutations accumulate when DNA is damaged. Bcl-2 also transport drugs out of cells, so when over-expressed, they will block chemotherapy
Term
What transcribes miRNAs?
Definition
RNA polymerase II
Term
Where are many miRNA genes located?
Definition
in introns of other genes
Term
What happens if miRNA is always expresse?
Definition
Can act as an oncogene and ablate the activity of a protein which regulates cell growth; thus getting uncontrolled cell proliferation
Term
If you lose the expression of miRNA?
Definition
Can act as a tumor supressor, a growth stimulatory gene may be constitutively expressed.
Term
What are tyrosine kinase viral oncogenes located on the membrane?
Definition
v-src
v-fms
v-erbB
Term
What is a growth factor viral oncogene and its located in the cytoplasm?
Definition
v-sis
Term
What is a GTP-binding protein viral oncogene and its located in the membrane or cytoplasm?
Definition
v-ras
Term
What is a serine/threonine kinase viral oncogene located on the membrane or cytoplasm?
Definition
v-raf
Term
What is a transcription factor viral oncogene located in the nucleus?
Definition
v-fos
v-jun
v-myc
Term
What happens with mutated c-raf?
Definition
Leads to an improper activation of MAPK
-Mutated raf is active without ras
-Mutated raf kinase activity is constitutive
- Mutated such that raf is over-expressed
Improper activation of MAPK would lead to initiation of cell growth at improper times
Term
What mutations lead to autocrine stimulation?
Definition
1) sis
2) hst
3) int-2
Term
What are transcription factors that can be oncogenes if altered form exists, inappropriate expression, or increased or decreased ability to bind DNA also will affect cell growth?
Definition
1) fos
2) myc
3) jun
4) max
5) ski
6) min
7) myb

Fos(tered) Myc(el) Jun(berg) Max(amizes) Ski(ing) Min(us) Myb(e the summer)
Term
What has lost its GTPase activity and what does this mean?
Definition
v-ras
-Ras protein is constitutively active
-GAP cannot activate GTPase activity in v-ras
Term
Normal cells can be transformed by the introduction of either c-ras or v-ras by over-expression, how do they differ though?
Definition
-GAP can overcome transformation by c-ras
-GAP cannot overcome transformation by v-ras
Term
What regulates the E2F family of transcription factors?
Definition
Rb
Term
What does Rb do?
Definition
Binds to E2F and blocks transcription of genes required for the G1 to S cell cycle transition
Term
What happens when Rb is phosphorylated?
Definition
It dissociates from E2F, and transcription is initiated so cells can enter the S phase
Term
What regulates Rb phosphorylation such that Rb is only phosphorylated at a specific point in the cell cycle?
Definition
cyclin complexes (cdk2 and cyclin A)
Term
If Rb is absent?
Definition
This regulatory step at the G1/S boundary is missing and cell proliferation will result.
Term
What does p53 do?
Definition
1) Recognizes DNA damage, then activating p53 transcription factor activity
2) p53 stimulates the transcription of GADD45 which repairs the damaged DNA
3) p53 stimulates the transcription of p21 (a cyclin kinase inhibitor, CKI) which blocks cdk-dependent phosphorylation of Rb, thus arresting cells in the cell cycle
4) if damage cannot be repaired, apoptosis-promoting genes are transcribed
Term
Loss of some miRNA expression can lead to overexpression of?
Definition
Bcl-2 and ras leading to cancer, hence miRNA defects are oncogenes
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