Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
148 Cards in this Set
- Front
- Back
|
nuclear receptors
|
bind esm that are hydrophobic that readily cross PM and are lipid soluble:
testosterone, progesterone, estrogen, mineral corticoids, cortisol, thyroid hormone, retinoids, and vit d all transcription factors --> regulates DNA transcription have a conserved DNA-binding domain (DBD or C domain), A-F domains: A/B is variable AF1 and AF2 are activation function domains ligand binding domain (LBD, E), D and F are highly variable --> D contains nuclear localization signal, some receptors don't have F |
|
|
orphan nuclear receptors
|
nuclear receptors proteins with unknown ligand that binds but have same molecular structure
|
|
|
Inactive nuclear receptor
|
binding of inhibitory protein, inactive conformation
|
|
|
Active nuclear receptor
|
binding of ligand causes release of inhibitory protein, movement to nucleus, bind DNA, and binding of co-activators --> Tc
|
|
|
Early primary response to steroid hormone
|
steroid hormone ligan binds to nuclear receptor --> complex activates primary-response genes --> synthesis of proteins in primary response
|
|
|
Delayed secondary response to steroid hormone
|
Effect of cycloheximide primary response protien --> shuts of primary response genes and turns on secondary response genes --> secondary response proteins
|
|
|
steroid hormones can alsobind to membraine-associated receptors to elicit biological responses
|
estrogen, progesterone, etc..
by activating MAP kinase, cAMP, PKC, Calcium channels etc |
|
|
Cell surface receptors
|
Ligand-gated channels (Ion-chaneel coupled receptors), G-protein-coupled receptors, Enzyme-coupled receptors
|
|
|
Ligand gated channels
|
ESM (often NT) binds to ion channel protein and opens or closes channel,allowing entry or exit of ions
|
|
|
G-protein- coupled receptors
|
spans membrane
involves receptor, g protein, and enzyme ESM (a first messenger) actvated receptor and g protein, then enzyme --> 2nd messenger |
|
|
enzyme-coupled receptors
|
involves ESM in form of a dimer
first activates catalytic domain of enzyme OR activates enzyme by association of receptor via ESM |
|
|
scaffolds
|
bring signaling proteins together to increase efficiency, precision, and speed
|
|
|
signaling protiens
|
are molecular switches, turn activity on or off
|
|
|
intracellular signaling cascades
|
organization of some protein kinases
|
|
|
Effect of ESM binding PM receptor
|
ESM binds PM receptor, activations of receptor, activity of proteins on, relayed from receptro to proteins bound by scaffold, generatio of 2nd messenger, 2nd messenger amplifies signal, signals bind to effectors, regulates Tc
|
|
|
Assembly of signaling complexes (scaffolds)
|
depends on presence of specific binding domains on signaling proteins
|
|
|
4 common binding domains in intracellular signaling proteins
|
PH = pleckstrin homology domain
PTB = phosphotyrosine-binding SH2 = Src homology 2 domain SH3 = Src homology 3 domain |
|
|
PH domain
|
recognizes phophorylated inositol lipid (PIPII or PIPIII)
|
|
|
PTB and SH2 domain
|
recognizes phopho-Tyr domain
|
|
|
SH3 domain
|
recognizes proline-rich motif
|
|
|
GTP-binding proteins (G-proteins)
|
Binding of GTP switches protein from inactive to active state. G proteins contain intrinsic GTPase activity, hydrolyzing GTP to GDP switches off activity
|
|
|
Protein kinases and phosphatases
|
binding of ATP either turns on or off protein by phosphorylation. often organized into phosphorylation cascades, where one protein kinase then phosphorylates the next protein kinase
|
|
|
Phosphoryl activation switches
|
sometimes the binding of a protein to a phosphorylated residue (usually Tyr) via a PTB or SH2 domain is enough to activate a protein
|
|
|
as number of cooperating molecules to activate a response increases, percentage of maximum activation of target protein..
|
increases
|
|
|
G-protein-coupled receptors activate ..
|
heterotrimeric g-proteins
|
|
|
GTPase activity of G-protein alpha subunit is regulated by
|
SGR (regulators of G-protein signaling)
|
|
|
cAMP regulates cAMP-dependent protein kinase (PKA)
|
takes 4 cAMP to activiate regulatory subunit... catalytic subunit then phosphorylates CREB in nucleus to regulate Tc
|
|
|
G(alpha)q
|
activates phospholipase C-Beta
hydrolyzes PIP2 via phospholipase C-Beta to generate diacylglycerol and IP3 second messengers. Diacylglycerol activates protein kinase C IP3 goes to ER to release Ca2+ via IP3-gated calcium channels All regulate muscle activity |
|
|
Protein Kinase C (PKC)
|
2nd messenger made from activated diacylglycerol
Ser/Thr protein kinase activated by diacylglycerol, calcium and membrane phospholipid. It phosphorylates Tc factors, metaboli enzymes, and other proteins |
|
|
Calcium
|
is a ubiquitous second messenger
triggers muscle contraction and secretion and regulates intracellular signal pathways |
|
|
Calcium concentrations
|
in cytosol is LOW (10-7), so can act as a 2nd messenger. its conc is increased 10-20 fold when ER lets Ca out via IP3 gated channels
its conc is 10-3 in ER and outside cell |
|
|
calcium pumps
|
in mitochondria, er, and PM
|
|
|
3 types of calcium channels that mediate ESM-stiumulated elavation of intracellular Ca2+
|
IP3-gated channels in ER
Voltage-dep channel in PM: opens in response to membrane depolarization Ryanodine receptors in ER: activated with a rise in intracellular Ca2+ (ca-induced ca release) |
|
|
with increasing amounts of vasopressin, calcium output....
|
increases concentration and frequency, not amplitude
|
|
|
Calmodulin
|
Binds Ca2+ allosterically and cooperatively!! (NOT covalently)
Calmodulin targets: PM Ca2+ pumps, calmodulin-dep protein kinases, and others NOT an enzyme: it binds other proteins and alters their activity. so it binds calcium, binds Ca pump on PM, allows release of calcium into extracellular space |
|
|
calmodulin-protein kinase II
|
calmodulin activates cAM protein kinase II --> it is important in memory
|
|
|
G(alpha) i
|
inhibits adenylyl cyclase, decreases cAMP
|
|
|
G(beta, gamma) i
|
are activated by the G-protien-coupled receptor: acetylcholine receptor!!
activated G(beta, gamma) i activates K+ channels acetylcholine has inhibitory effect on heart |
|
|
G(alpha) olf
|
activates adenylyl cyclase in olfactory neurons, increases cAMP which then binds to cyclic nucleotide-gated cation channels bringing Sodium and calcium in and Cl- out...depolarizes neuron --> nerve impulse. regulates smell and vision!!
why humans can distinguish 10,000 distinct smells via olfactory neurons the receptor is on surface of cilia on olfactory neuron. the odorant molecule is the ESM |
|
|
amplification
|
one ESM generates lots of 2nd messengers!
|
|
|
how to turn off signals mediated by G-receptors/proteins?
|
phosphodiesterases, phosphatases, Ca2+ pumps
WAYS: 1. ligand dissociates off receptor 2. receptor "uncouples" from G-protein --> desensitization 'adaptation' cuz ligand is still bound but receptor is unable to signal 3. receptor internalized! |
|
|
Enzyme-linked cell-surface receptors
|
cytosolic domains of these either has intrinsic enzyme activity or associates directyl with an enzyme. span membrane ONCE
|
|
|
Receptor tyrosine kinases
|
all have tyrosine kinase activity
activation by ESM 1. dimerization of inactive recptor tyrosine kinases 2. autophosphorylation (phosphorylate each other) 3. this phosphorylation alters conformation and increases kinase activity 4. phospho-tyrosines create high-affinity docking sites for binding of signaling proteins 5. trasient association of signaling complex` |
|
|
Insulin and IGF-1 receptors bind ..
|
intermediate adaptor protein (IRS1)--> the activated insulin or IGF-1 receptor phosphorylates IRS1 --> docking sites for other signaling molecules
|
|
|
Phosphorylated tyrosines serve as docking sites for
|
proteins with SH2 domains!!
ie GAP, PI 3-kinase, phospholipase C (PLC) |
|
|
How to activate Ras
|
activate a tyrosine kinase receptor
1. bind Grb-2 to phosphorylated tryrones via SH2 domains 2. Grb-2 binds to SOS via SH3 domain 3. SOS (GEF) is brought into vincinity of inactive Ras and releases GDP from Ras and binds GTP on Ras to activate 4. GAP hydrolyzes GTP to GDP to inactivate Ras. |
|
|
Activated Ras causes..
|
downstream Ser/Thr phosphorylaition cascade
ie. mitogen-activated protein kinase (MAPK) pathway |
|
|
Mitogen-activated protein kinase (MAPK) pathway
|
activated Ras activates Raf, MEC, and Erk to regulate protein activity and gene expression. Mutations in Ras cause cancer. Activation of Raf, MEC, and ERK are produced by P of Ser/Thr AAs
|
|
|
Deactivation of Ras
|
Dissociateion from Receptor
Phosphatase: dephosphorylation of receptor Accelerating GTP --> GDP |
|
|
Receptor Tyrosine Kinases activate PI 3-kinases by
|
Regulatory subunit of PI 3-kinase binds to phosphorylated receptor via its two SH2 domains binding to the phosphorylated Tyrosines on the receptor. Binding alters the conformation of PI 3-kinase which activates it
|
|
|
Activated PI 3-Kinase
|
promotes phosphorylation of PIP2 --> PIP3
PIP3 binds to and activates proteins via their PH domains |
|
|
Tyrosine kinase-associated receptors
|
receptor is associated with Jak (Janus Kinase)
ESM include the cytokines -- interferons, interleukins, erythropoietin, and select hormones, growth hormone, prolactin binding of cytokind causes receptors to dimerize, associated Jaks are brought together to cross-P each other on tyrosines. Active Jak P's receptor, creating docking sites for STATs and other proteins |
|
|
STAT
|
signal transducer and activators of Tc; latent Tc factor.
STATs dock to P tyrosines on tyrosine kinase-associated receptor via SH2 domain STATs are then P'ed by Jaks STATs dissociate from receptor and dimerize Migrate to nucleus and other gene regulatory proteins, target gene Tc |
|
|
Cytokine effects via Jak-STAT pathway via tyrosine kinase-associated receptors
|
immune response to viral infection
RBC production Stimulates growth and production of IGF-1 Stimulates milk production Immune response to vacterial infection |
|
|
Receptor-like tyrosine phosphatases
|
Unclear what ESM is!?
Some receptors have no extracellular domains and are only intracellularly regulated via SH2 domains All have intracellular tyrosine phosphatase domains |
|
|
Receptor Serine/threonine kinases: TGFBeta family
|
regulate pattern formation (development, morphogens), proliferation, cell death, extracellular matrix formation
1. ESM binds to and activates Type II receptor 2. Type II recruits and P's and activates kinase activity of Type I receptor. 3. Type I receptor P's Smad3 or 2 protein 4. P'd Smad binds co-Smad4, and translocates it to nucleus where it activates target genes |
|
|
Receptor guanylyl cyclases
|
activated by natriuretic peptides that dilate blood vessels
suluble guanylyl cyclase activated by NO, also generated from nitroglycerine GTP --> via NO --> cGMP increase in heart Regulates PDE, ion channels, PK |
|
|
Pathways that regulate proteolysis
|
notch receptors
regulated proteolysis of B-catenin NF-kB signaling pathway |
|
|
Notch receptor
|
regulates proteolysis
play major role in development of most tissues nerves cell are developed from epithelial cells by producing Delta signal that binds onto Notch receptor on epithelium cell and inhibits these cells |
|
|
Nerve cell development from epithelial cells
|
Nerve cell express Delta signal that binds to Notch receptor on adjacent epithelial cell,
2. gamma-secretin cleaves the notch receptor 3. Notch receptor tail migrates to nucleus to CSL protein to activate gene Tc |
|
|
Alzheimers
|
mutation of presenilin-1 required for the final cleavage to activate Notch causes cleavage of B-amyloid precursor protein (APP) a membrane protein expressed in neurons. Peptide fragment is released into Extracellular space in brain and they for amyloid plaques to cause nerve damage
|
|
|
regulated proteolysis of B-catenin
|
requires regulated proteolysis
In absence of extracellular signaling molecule Wnt, B-catenin is P'ed and targeted for proteosomal degradation. --> regulates Tc In presence of Wnt, Wnt binds to Frizzled receptor, leading to inactivation of GSK3Beta, and accumulation of unP'ed B-catenin B-catenin is stable and nmoves into nucleus and activates target genes. it functions as a co-activator of other TFs. |
|
|
NF-kB
|
latent transcription factor sequestered in cytoplasm by an inhibitor IkB
|
|
|
NF-kB Pathway
|
requires the ubiquitylation and degradation of P'ed IkB in proteasome. NF-kB is freed and is a transcription factor!
|
|
|
TNFalpha trimer
|
Tumor Necrosis Factor is produced in stressful situations. this is the ESM for NF-kB...when NF-kB is bound to DNA, Tc occurs and produces inflammatory responses
|
|
|
Cell Cycle
|
M - mitosis and cytokinesis
G1 - "Gap" phase S - "DNA replication" G2 - Duplication |
|
|
Events of Euk Cell Cycle
|
M Phase: Prophase, prometaphase, metaphase, anaphase, telophase
Interphase: G1, S, G2 |
|
|
Ways to study cell cycle
|
Yeast:
b/c proliferate in haploid state (1N) easy to study mutations divide quick Cell-division-cycle (cdc) genes discovered in yeast divide at low temps not high way to identify crucial genes for cell cycle |
|
|
What type of cells used to study cell cycle
|
tumor cells
normal tissues immortialized cell lines S phase recognized by H-Thy incorporation or artificial Thy analog brdU into newly synthesized DNA --> labeling index: how many cells in S phase!! |
|
|
How to measure amount DNA in cell
|
Flow cytometry. Dye that binds DNA during S phase
|
|
|
cell cycle control systems
|
clock, initiate stages in correct order, each stage triggered once, stages triggered in complete, irreversible manner, back-up mechanisms, sensitive to environmental condictions,
esm signals |
|
|
Checkpoints in cell cycle
|
arrest cell cycle if previous step is not complete!
G2/M CheckPoint: Is all DNA replicated? Is environment Favorable? Metphase-toanaphase Checkpoint: Are all chromosomes attached to the spindle? G1 Checkpoint: is environment favorable? |
|
|
Cyclin-dependent Kinases (Cdks)
|
control cell-cycle
They are cyclically activated, S/T protein kinases activated by cyclin cell cycle progression is regulated by P'tion of specific proteins by Cyclin/cdk Cdk activty terminated by cyclin degradation |
|
|
Cyclin
|
activates Cdk and directs Cdk to specific targets.
concentrations oscillate during cell cycle Hi during G1, S, Mitosis, Low during metaphase-anaphase and start of G1 G1 cyclin, G1/S cyclin, S cyclin, A cyclin, M cyclin |
|
|
Cdk activation
|
binding of cyclin and P'tion by Cdk-activating kinase (CAK), a S/T kinase
Wee 1 inhibits Cdk by phosphorylating Tyr on Cdk Cdc25 promotes Cdk by dephosphorylating the site Wee 1 P'ed!! |
|
|
Cdk inhibitor proteins
|
inhibit Cdk activity by p27, p21, etc it binds cyclin/cdk
|
|
|
Cdk/cyclin inactivated by proteolysis
|
p27 is ubiquitinated by SCF after it is phosphorylated
G1 cyclin is degraded by being ubiquitinated by SCF SCF is continually active during cell cycle it targets phosphorylated things |
|
|
Anaphase-promoting factor (APC)
|
regulates proteolysis of Cdk
APC catalyzes ubiquitylation of S and M cyclins and other regulatory proteins (securin). APC is active late in mitosis by Cdc20 and by phosphorylation |
|
|
Cells held in G1 by....
|
Cdk inhibitor proteins such as p21 and p27
Absence of cyclins other inhibitors |
|
|
Neurons and muscle cells cell division
|
contstant G0 state in which Cdk and cyclin expression is terminally off
|
|
|
Entry into S phase by...
|
Mitogens (growth factors)
activation of MAPK pathway 1. PDGF binds to receptor tyrosine kinase 2. activates Ras 3. Ras activates MAP kinase kinase kinase, MAP kinase kinase, MAP kinase, activating expression of Myc protein 4. Myc promotes expression of G1 cyclin, SCF subunit to destry p27, and E2F gene, all entry into S phase! |
|
|
Cell proliferation regulated by Pi-3 kinase pathway!
|
generated Akt regulates cell division
stimulated by receptor tyrosine kinase or SOMETIMES GPCRs |
|
|
Insulin or IGF-1 binding to IRS1 regulations cell division too
|
by generating Akt
|
|
|
How activated Akt leads to cell proliferation
|
phosphorylates p27 --> degredation
phosphorylates FOXO1 --> degredation Myc binds to G1 cyclin gene, increased G1 cyclin, activation of G1/Cdk |
|
|
Retinoblastoma (Rb)
|
Blocks progression into S phase. G1-cyclin/Cdk P's active Rb which release E2F in an active form. E2F binds to promotors of many genes that encode proteins for S phase entry (G1/S and S-phase cyclins.)
|
|
|
Inhibition of E2F by Rb releived by...
|
ESMs
Positive Feedback! |
|
|
Rb
|
First tumor surpressor identified
|
|
|
p27 degredation
|
by G1/S- and S-cyclin
|
|
|
G1 Checkpoint
|
Block activity of G1/S cyclin/Cdk and S-cyclin/Cdk via DNA damage
IF DNA is damaged, protein kinases are made that activate p53. 1. p53 arrests cell cycle by producing p21 gene 2. p21 inactivates G1/S-Cdk and S-Cdk 3. p53 also targets DNA repair genes Mdm2 can degrade p53 Mutations can occur in p53 and result in cancer |
|
|
Activators of p53
|
DNA damage, hypoxia, ribosome levels, NT triphosphate levels, inactivating mutation of Rb
|
|
|
S-cyclin P'tion of ORC prevents...
|
reformation of pre-RC
|
|
|
Mitosis activated by
|
M-phase Cyclin/Cdk
M-cyclin increases during G2, resulting in formation of M-cyclin/Cdk. M-cyclin/Cdk is maintained in an inactive state until entry into mitosis 1. M-cyclin allosterically binds to Cdk 2. Cdk-activating kinase (CAK) and Wee1 phosphorylate M-Cdk but its still inactive 3. Cdc25 dephosphorylates the phosphate put on by Wee1 to create active M-cyclin/Cdk |
|
|
G2 Checkpoint
|
delays entry into mitosis in response to incomplete DNA replication. Damaged DNA sends signal that prevents activation of Cdc25.
1. p53 to repair damaged genes |
|
|
M-cyclin/Cdk P's specific proteins to
|
induce assembly of mitotic spindles
Ensure that replicated chromosomes attach to spindle trigger chromosome condensation Trigger nuclear envelope breakdon triggger actin skeleton reorganization Trigger reorganization of Golgi and ER |
|
|
Principle stages of M phase
|
separate and distribute chromosomes to each daughter cell receives an identical copy of genome
|
|
|
Prophase
|
chromosome condensation mediated by m-cyclin/Cdk P'tion of condensins
|
|
|
Prometaphase
|
breakdown of nuclear envelope beings with M-Cyclin/Cdk mediated P'tion of nuclear lamina,
1. breaking down of nuclear envelope, MTs can interact with chromosomes |
|
|
Metaphase
|
sister chromatids held together by cohesin proteins, aligned at equator.
kinetichore detect if sister chromatids are attached to spindles |
|
|
Kinetichore
|
large protein complex that assemgles at centromeres: binds MTs and monitor MT attachment to Sister chromatids. important in checkpoint between metaphase and anaphase
|
|
|
Anaphase
|
sister chromatids are separated by shortening kinetichore MTs.
separation triggered by anaphase promoting complex (APC) that inactivates cohesin that attaches sister chromatids |
|
|
APC role in mitosis
|
separation of sister chromatids by inactivating cohesin, triggers anaphase
1. inactive APC is P'ed by cdc20 and helps to degrade securin and activate separase to cleave cohesins |
|
|
metaphase-anaphase checkpoint
|
are all chromosomes attached to spindle? APC will not be activated because Mad1 and 2 are recruited...will not detach sis. chromatids if they arent
|
|
|
Telophase
|
Nuclear envelope reassembles as a result of INACTIVATION of m-cyclin/cdk and action of phosphatases
|
|
|
APC promotes
|
degredation of M-cyclin and other regulatory proteins , allowing for dephosphorylation of lamins and condensin and disassembly of spindle in cytokinesis
|
|
|
Cytokinesis
|
spindle is disassembled, chromosomes decondensed
|
|
|
What happens in G1?
|
cells grow. Cyclin/Cdk is surpressed by absence of cyclin and/or presence of CDIs
|
|
|
how is cell growth regulated ?
|
by PI-3 kinase pathway --> Akt for cell survival, growth , and division.
|
|
|
apoptosis
|
programmed cell death, bone marrow and intestinal cells die each year, necessary during embryonic development
|
|
|
Atresia
|
99% of oocytes die by apoptosis only 450 are ovulated! of the 800,000
|
|
|
significance of apoptosis
|
atresia, cancer, neurodegenerative disease, heart attack/stroke, development, tadpole, mouse foot, autoimmune disease, irreparable DNA damage
|
|
|
Necrosis vs apoptosis
|
apoptosis:
cell shrinkage Membrane integrity maintained role for mitochondria and cyt c No leak of lysosomal enzymes characteristic nuclear changes apoptotic bodies form DNA cleavage Activation of specific proteases regulatable process evolutionarily conserved dead cells ingested by neighboring cells Necrosis: cell swelling membrane integrity lost no role mitochondria leak of lysosomal enzymes nuclei lost apoptotic bodies do not form No DNA cleavage no activation of proteases not regulated not conserved dead cells ingested by neutrophils and macrophages |
|
|
caspase
|
involved in apoptosis
cysteine at active site . aspartic in target protein cleaves itself, target proteins caspase cascade: 1.initiator caspase -->amplification tightly regulated 2. executioner caspase 3. cleraves cytosolic proteins and nuclear lamins |
|
|
first initiator caspase activated?
|
initiator caspases oligermerize w/in adaptor, activated when in proximity to each other
|
|
|
Two methods of caspase activation
|
Extrinsic (receptor mediated)
Intrinsic (mitochondrial |
|
|
Extrinsic caspase activation
|
activation of cell-surface "death receptors"
1. ESM activation of death receptor 2. binding of intracellular adaptor molecule to death domain of death receptor 3. adaptor recruits and binds multiple copies of procaspase-8 that is autoactivated and is "initiator caspase", 4. downstream effector caspases activated 5. cell death General: procaspases aggregate triggered by adaptor and become active |
|
|
Instrinsic caspase activation
|
activated by
DNA dmaage, treatment of cells with chemotherapeutic agents, groth factor withdrawal, reactive ocygen species Release of cyt c from mitochondria and initiation of caspase cascade regulated by Bcl2 family of proteins |
|
|
extrinsic receptors
|
Fas
TNF-alpha can either induce apoptosis or cell survival (NFkB) |
|
|
intrinsic apoptosis pathway
|
cyt c released from mytochondria by some sort of signal, apaf1 adaptor binds cyt c, procaspases9 binds adaptor and aggregates, activation of procaspase and its released to initiate caspase cascade.
|
|
|
Bcl-2 proteins regulate cyt c release
|
either inhibit apoptosis or stimulate
Inhibit Bcl-2, and Bcl-XL (4 BH domains) Stimulate BH123 (3 BH domains) BH3 only (1 BH domain): inhibit Bcl2, activate BH123 |
|
|
Inhibitors of Apoptosis (IAPs)
|
prevent accidental apoptosis
bind to and inhibit active caspases |
|
|
IAP antagonists
|
inhibits IAPs by binding to them --> allows apoptosis to occur
|
|
|
How are BH3 and BH123 activated
|
DNA damage and oxidative stress
|
|
|
p53 role in apoptosis
|
DNA damage activates kinases that promote phosphorylation of p53 which stabilizes p53 and produces p21 protein which arrests cell cycle in G1. this results in apoptosis via BH3 only and Fas ligand production
|
|
|
FOXO1 role in apoptosis
|
in absence of ESM, expression of FOXO1 causes apoptosis
|
|
|
Reduced apoptosis because:
|
mutated/inactive p53
overexpression of anti-apoptotic proteins: IAPs, Mdm2 Constitutively active anti-apoptotic Akt: P's FOXO1 to red;uce Fas ligand expression Excessive expression of Bcl2 from chromosomal translocation |
|
|
Cancer cells
|
refelct their origin
derive from a single abnormal cell |
|
|
Clonal evolution
|
evaluation of chromosomes in tumor cells
ie chronic myelogenous leukemia : have leukemic white blood cells with "Philadelphia" chromosome translocation between long arms of 9 and 22 |
|
|
Epigenetic change exs
|
imprinting and x-chromosome inactivation
|
|
|
Most cancers are initiated by genetic change
|
shared abnormality in DNA sequence that distinguishes from normal cells. Mutagens that cause cancer are carcinogens
|
|
|
Environmental factors
|
70% carcinogens
largely environmental not genetic |
|
|
Cyt P450
|
activates some carcinogens
|
|
|
Ames test
|
Potential mutagen + activating liver extract + cyt P450
ability to create revertants --> mutagenesis |
|
|
Tumor initiators
|
do not themselves give rise to a tumor, but cause latent genetic damage (are mutagenic)
ie tobacco smoke |
|
|
Tumor promoters
|
can cause cancer if they are applied after treatment with a tumor initiator. They are not mutagenic (do not dmage dna)
|
|
|
Phorbol Esters (TPA)
|
tumor promoter creates PKC
|
|
|
Viruses and cancer
|
alter dna directly or act as tumor promoter
|
|
|
Bacteria
|
ulcrs and stomach cancer (helobacter pylori
|
|
|
Onset of cancer
|
Single mutation not enough to cause cancer
development of cancer requires mutations in many genes Most cancers are sporadic and have no basis in heredity Development is slow Progression requires successive roudns of mutation and natural selection Unstable depend on defective control of cell death or cell differentiation cancer cells maintain/acquire telomerase activity Mutations in BRCA genes --> ovarian and breast cancer Mutations in Rb --> Retinoblastoma in young kids |
|
|
Stem cells and tumor onset
|
stem cells fail to produce more stem cells --> tumor of transit amplifying cells
or stem cells fail to differentiate --> tumor tumor is benign unless mutation |
|
|
Proto-oncogenes
|
normal genes that promote cell growth and mitosis
mutations in proto-oncogene increases activity of its product protein (gain-of-function) and is called an oncogene. ie Ras, EGF receptor (Her2), Myc, Bcl2 Cancer: DNA mutations that positively effect expression of oncogenes (activating mutations of proto-oncogenes) |
|
|
Tumor Suppressor genes
|
inhibit cell division. usually TFs or intermediates in signaling pathays. Mutated tumor suppressor genes (loss-of-function) they drive cell towards cancer. Effect is ressicive and requires both genes to be effective.
ie Rb, BRCA, APC, p53 Cancer: DNA mutations that negatively effect expression of tumor suppressor genes (inactivating mutations) |
|
|
Mutations in APC...
|
cause stabilization of B-catenin which results in increased Tc of its target genes including Myc and G-cyclin
APC is tumor suppressor gene |
|
|
Her2
|
oncogene derived from EGF receptor in which ESM is missing....constituitively active...breast cancer
|
|
|
Ras
|
Proto-oncogene...mutated in 1/4 of cancers
|
|
|
p53
|
tumor supressor gene involved in cell-cycle control, apoptosis, and genetic stability
mutated in 50% all cancers p53 is activated by DNA damage, mdm2 is degraded and p53 binds to p21 gene. p21 binds to G1/Cdk arresting cell cycle P53 also codes for BH3-only and Fas ligand |
|
|
E-cadherin
|
tumor suppressor gene: promotes cell-cell adhesion in healthy cells and mediates contact inhibition
|
|
|
Multidrug resistance
|
cancer cells become resistant to chemotherapy
|
|
|
Gleevac
|
Abl-selective tyrosine kinase inhibitor used to treat chronic myelogenous leukemia
|
