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;
109 Cards in this Set
- Front
- Back
|
2 Ways a cell dies |
Necrosis apoptosis |
|
|
Necrosis |
cell death that occurs in response to an acute insult trauma, lack of blood supply -> messy |
|
|
apoptosis |
programmed cell death systematically destroyed from within -> clean |
|
|
Apoptosis occurs in |
development: half neurons are killed, tadpole- how it loses tail after development: keeps tissues in steady state, rat liver experiment ( when part of liver removed, cells increase cell cycle, when rat stimulated cell division- apoptosis increased) If a cell detects a lot of DNA damage, triggers apoptosis to reduce risk of cancer |
|
|
Family of proteases that can start the apoptosis cascade |
caspases |
|
|
Caspases |
active site is a cysteine targets a.a. (aspartic acid) C-ASP-ases cuts up protein synthesized in cell as inactive precursors that are then only activated in apoptosis |
|
|
2 major categories of caspases |
initiator caspases executioner caspases |
|
|
initiator caspases |
exist as inactive monomers signaling causes oligomerization which activates them active executioner caspases by protein cleavage |
|
|
executioner caspases |
exist as inactive dimers get cleaved by initiator caspases - now active cleave a lot of target proteins |
|
|
There are over 1000 target proteins that are cleaved in the protease cascade: |
nuclear lamina (breaking nucleus) an inhibitor of an edonuclease (free/active to cleave DNA) cytoskeletal proteins (breaking structure of cell) cell-cell adhesion proteins (round up phagocytic cell can target) |
|
|
2 main methods for activating the initiator caspase |
extrinsic pathway intrinsic (mitochondrial) pathway |
|
|
extrinsic pathway |
extracellular signals binds death receptor cytosolic side of receptor activates apoptosis |
|
|
intrinsic (mitochondrial) pathway |
in response to stress (DNA damage) cell releases protein from mitochondria protein is cytochrome C |
|
|
Control of Intrinsic pathway |
Bcl2 family of proteins that control the release of cytochrome C some Bcl2 proteins are pro apoptotic (enhance release of cytochrome C) Some are anti apoptotic (blocking release of cytochrome C) - biding to and inhibiting pro- apoptotic The balance of these determine whether a mammalian cell lives or dies |
|
|
Activation of caspases is irreversible and leads to certain death so the cell wants to ensure that they are only activated when appropriate by: |
inhibitors of apoptosis (IAPs)- bind to caspases and inhibit or ubiquitylate - inhibiroy threshold caspases must overcome anti -IAPs- produced in response to apoptotic signals |
|
|
Survival factors |
extracellular signals that promote cell survival automatically adjusted to number of target cells |
|
|
Cells undergoing apoptosis are recognized by phagocytic cells: |
1. the negatively charged phspholipid phosphatidylserine is displayed on the outer leaflet of the plasma membrane - normally in inner leaflet caspases cleave some protein involved in distribution of phopholipids (flippase) 2. extracellular bridging proteins bind to the phosphatidylserine and to receptors on macrophages - triggers their cytosketelton to rearrange to engulf apoptotic cell |
|
|
Excess apoptosis can lead to disease and too little apoptosis cal lead to disease |
excess: heart attack, stroke, (lots of necrosis) degenerative disorders too little: tumors , autoimmune disorders |
|
|
Direct cell-cell interactions |
transmembrane protein bind to other other proteins |
|
|
interaction with extracellular matrix |
Network of proteins and polysaccharides excreted from cells connective tissue= matrix transmembrane protein extends out |
|
|
Cell-cell junctions |
Anchoring junctions (adherins, desmosomes) tight junction gap junction |
|
|
adherens |
connect actin to actin |
|
|
desmosomes |
intermediate filaments to intermediate filaments |
|
|
tight junction |
sealing 2 cells together |
|
|
gap junciton |
create pore between cells |
|
|
Cell-matrix junctions |
anchoring junctions - actin -linked cell-matrix junction: connects actin to extracellular matrix hemidesmosomes: connects intermediate filament to matrix |
|
|
Interactions depend on |
transmembrane adhesion proteins |
|
|
transmembrane adhesion proteins |
span membrane intracellular - cytoskeleton extracellular - protein/matrix |
|
|
2 main families of transmembrane adhesion proteins |
cell-cell attachment: cadherins cell-matrix attachment: integrins |
|
|
Cadherin family |
requrie Ca2+ found in animals classical cadherins ( E-cadherin, N-cadherin, P-cadherin) non classical - protocadherins, desmogelins |
|
|
Cell-cell junctions are like velcro |
binding occurs at the very N-terminal domain, structure of the last cadherin domain allows for binding, relatively long and linear = far apart |
|
|
Calcium binds bear each hinge in between the extracellular cadherin domains |
prevents hinges from flexing individual interactions are weak, but many weak bonds in parallel form strong connections between cells |
|
|
adherens junctions likely participate in mechanotransduction |
protein -protein interaction are not passive dynamic tension sensors regulate behavior mechanotransduction depends patially on changing shape of proteins when under tension |
|
|
Mechanotransduction |
alpha catenin= linker protein tension exposes site for vincolin -recruits more actin pulling on the junction makes its stronger |
|
|
Desmosomes role |
connecting the intermediate filaments to transmembrane protein non classical cadhersing - provide mechanical strength and abundant in tissues - heart muscle, epithelium (skin) |
|
|
Tight junctions function |
seals adjacent epithelial cells together prevents passage of molecules from one side of epithelial sheet to another prevent molecules in extracellular fluid from moving past the line of epithelial cells also prevent intramembrane proetins from diffusing to the opposite side of the cell. |
|
|
polarized epithelial cells: |
Basal - the base or basement - anchored to matrix or another tissue on bottom Apical - bathed in extreceullar fluid not attached to matrix or cells |
|
|
Tight junction intramembrane proteins |
short and fat, 4 transmembrane domains, want cells to be really close |
|
|
Gap junction |
channels connecting the cytoplasm between cells pore size 1.4nm -allows passage of small molecules (ions, sugars, nucleotides, vitamins, second messenger signaling molecules) |
|
|
Gap junction structure |
connexin protein: has 4 transmembrane domains, 6 connexin proteins -> connexon 2 connexon structures (1 from each cell) for the channel/gap many connexons cluster together like seive |
|
|
Gap junctions switch between open and closed |
regulated by pH, calcium concentration, membrane potential of each cell, important for immediate signaling between electrically excitable cells- action potential can spread from cell to cell quickly electrically coupled to synchronize (smooth muscle, heart muscle) |
|
|
Plasmodesmata in plants |
similar to gap junctions plant cells are surrounded by cell walls- extracellular matrix of cellulose and other polysaccharides therefore plants do not need anchoring junctions plasmodesmata are for cell-cell communications |
|
|
Extracellular matrix examples |
examples: bone and teeth, cornea, tendons, exoskeletons , jelly, wood |
|
|
The macromolecules that make the matrix are secreted by fibroblast cells : |
chondroblasts- form cartilage osteoblasts- form bone |
|
|
3 major classes of macromolecules |
1. Glycosaminoglycans (CAGs) (proteoglycans) 2. Fibrous proteins 3. glycoproteins |
|
|
Glycosaminoglycans (CAGs) |
large, charged sugars, mostly sugar with little protein |
|
|
Fibrous proteins |
primarily collagen |
|
|
glycoproteins |
other proteins, wit n-linked sugars mostly protein with little sugar |
|
|
Glycosaminoglycans structure |
unbranched polysaccharide chains, repeating disaccharide units, one is an amino sugar highly sulfonated, giving sugar a negative charge due to sugar chains which do not condense into globular domains, and highly negative charge-> occupy large volume compared to MW and fills most of E.C. space |
|
|
Simplest GAG |
hyaluronan |
|
|
hyaluronan |
extremely long sugar chain (up to 25,000 disaccharides) found in all adult tissue and fluids, highly abundant in early embryos synthesis: an enzyme complex in plasma membrane - synthesize directly in E.C. space used as a space filler during development, creates a cell free space into which cells can migrate |
|
|
All GAGs except hyaluronan are attached to proteins, proteoglycan synthesis |
ribosome synthesize into E.R. polysaccharide chains added in golgi delivered in vesicle to plasma membrane for exosytosis up to 95% of molecule is sugar |
|
|
Collagen |
family of fibrous proteins found in all multicellular animals major component of skin and bone structure: 25% of total protein 3 collagen polypeptides - triple helix each of 3 peptides -repeat of 3 a.a. Gly-x-y x is often proline y is often hydroyproline |
|
|
Glycine in collagen |
glycine in every 3rd position allows for the very tight coiling of three strands: only a.a. small enough to occupy interior space collage fibrils aggregate into a larger, cable like bundles= collage fibers |
|
|
Function of collagen |
resist tensile forces in skin: woven into basket pattern to resist stress in multiple directions in tendons: organized in parallel bundels in bone: organized orderly perpendicular bundles like plywood |
|
|
Other components of the ECM |
elastin fibronectin laminin |
|
|
elastin |
hydrophobic protein that is secreted and then cross linked, generating elastic networks abundant in arteries |
|
|
Fibronectin |
glycoprotein with multiple binding domains many binding domains, to organize ECM only one gene in humans but lots of alternative splicing |
|
|
Laminin |
protein complex that is primary organizer of a specialized ECM called basal lamina (think, tough flexible sheet of E.C.M.) |
|
|
Laminin structure |
bind to other ECM components nidogen and perlecan bind to transmembrane proteins integrin and dystroglycan alpha beta and gamma polypeptides twisted together into a cross always closley associated with cells |
|
|
Degrading the ECM |
required for tissue repair, cell migration, cell division, general replacement degraded by extracellular proteases that are secreted matrix metalloproteases and serine proteases act precisely by 2 methods: the protease is specific to certain ECM proteins (collagenases) and attach to plasma membrane (act locally) |
|
|
Integrins |
anchor the cell cytoskeleton to the ECM transmit mechanical and molecular signals |
|
|
Integrin structure |
2 associated subunits: alpha and beta in humans 24 integrins, 23 linked to actin - only 1 links to intermediate filaments (hemidesmosomes) keratin - in epithelial cells |
|
|
Integrins can switch between an active and inactive state |
in active : cytoplasmic tails are hooked together active: adapter protein moves tails apart, dynamic proteins that either make/break connections |
|
|
Signaling that causes integrins to from inactive to active |
GPCR activates G-protein recruits talin talin changes intracellular of integrins |
|
|
Integrins cell matrix attachments |
like velcro principle - relatively weak interactions but clustered many integrins, dense plaque focal adhesion |
|
|
Cancer cell has 2 heritable properties |
1. undergo cell devision against all normal signals to stop 2. Invade and colonize surrounding tissue |
|
|
When a tumor is not yet invasive |
benign |
|
|
When the tumor cells acquire ability to invade surrounding tissue |
malignant "true" cancer |
|
|
Cancers are usually classified based on the tisue in which they originate: |
carcinomas - arise from epithelial tissue (breast, stomach, colon, lung) Sarcomas - arise from connective tissue or muscle Leukemias and lymphomas: arise from blood or nervous tissue Cancer cells arising from different cell types are usually very different diseases. |
|
|
How cancer starts |
a single cell obtains some change that allows it to proliferate more |
|
|
Somatic mutation |
makes cell different from all other clonal cells |
|
|
epigenetic changes |
heritable change in gene expression, chemical modification |
|
|
Cancer is microevolution therefore |
one mutation is not enough cancer requires many independent and rare genetic and epigenetic events to occur in a lineage of cells derived from one founder cell |
|
|
Steps of microevolutionary cancer progression |
1. one cell obtains random mutation 2. mutation gives cell selective advantage 3. new clonal mass, 1 cell gets 2nd mutation 4. even more advantage, divides even faster 5. repeat |
|
|
Given the mutation rate the incidence rate indicates: |
5-8 mutations to cause cancer |
|
|
Once cancer has already been formed, it becomes genetically unstable |
abnormally increased mutation rates, abnormal # chromosome duplications, deletions, translocations |
|
|
Properties of cancer cells |
loss of contact inhibition altered glucose metabolism ability to survive stress and DNA damage Require network of support cells around the tumor |
|
|
Loss of contact inhibition |
cancer cells are not inhibited by contact with neighbors |
|
|
Altered glucose metabolism of cancer cells |
consume glucose 100X normal rate does not go to oxidative phosphorylation less efficient but fast |
|
|
Ability of cancer cells to survive stress and DNA damage |
normally stress causes apoptosis cancer cells have mutations that disable normal apoptosis |
|
|
Cancer cells require a network of support cells around the tumor |
cancer cells only one is genetically different secreting signaling molecules to surrounding cells |
|
|
Metastasis |
most deadly and least understood aspect of cancer. the spread of cancer cells from origin to rest of body |
|
|
Metastasis steps |
1. cancer cell invade a vessel 2. moves through circulatory system 3. leave vessel 4. establish colony (limiting factor- not all will establish a colony) |
|
|
Mutations of cancer cells fall into 2 categories |
drivers and passangers |
|
|
drivers |
mutations that have a role in causing cancer |
|
|
passangers |
mutations that are by products |
|
|
2 broad categories of cancer critical genes |
proto-oncogenes tumor-suppressor genes genome maintenance genes |
|
|
proto-oncogenes |
normal: involved in cell proliferation mutated: gain of function, over expressed, over active - oncogene |
|
|
Tumor-suppressor gene |
normal: prevent to much proliferation mutated: loss of function , knock-out, inactive |
|
|
Genome maintenance genes |
normal: ensure proper chromosome duplication, separation, proof reading mutated: many mistakes in DNA much more likely get mutation in proto-oncogene or tumor suppressor genes. |
|
|
Discovering oncogenes |
It was discovered that viral infection cause tumors, but only small percentage of cancers caused by this, tumor viruses lead to discovery of oncogenes. Retroviruses passenger gene in viral genome |
|
|
retrovirus |
RNA genome, when infects cell, reverse transcriptase RNA-> DNA integrates into host genome |
|
|
passenger gene in viral genome |
v-src-gene from virus found similar gene in vertebrate genome c-src virus had picked it up, mutated it into an oncogene each gene had a counterpart proto-oncogene in a normal vertebrate genome |
|
|
experiment for discovering oncogene |
Take DNA from cancer cells put DNA fragments into new "almost" cancer cell when colony forms isolate the DNA and sequence Ras-mutated version can't hydrolyze GTP |
|
|
Discovering tumor suppressor genes |
came from rare cancer retinoblastoma childhood cancer, tumors develop in cells in immature retina hereditary form: multiple tumors both eyes non-hereditary form: only 1 tumor and 1 eye karyotypes of cancer cells from non-hereditary body cells from hereditary -chromosomal deletion rb- regulation of cell cycle |
|
|
Discovering cancer genes |
analysis of mRNA levels can find changes in gene expression. in addition to point mutations, chromosomal rearrangements can occur key is to sequence many tumors to find commonly mutated genes |
|
|
Current understanding of cancer cells |
accumulation of about 10 gene mutations increase in genetic instability increase chance of 1 cell gaining 7-10 mutations. current estimate: about 300 cancer-critical genes in human genome (1% of gene) signaling proteins, receptors, kinase, transcription factors, DNA repair enzymes |
|
|
Some common pathways in cancer cells |
Rb pathway P13K/Akt/m TOR pathway p53 pathway myc pathway |
|
|
Rb pathway |
Rb- controls cell devision |
|
|
PI3K/Akt/m TOR pathway |
normal function: activate cell growth in response to signals mutate anything in pathway signaling occurs without signals |
|
|
p53 pathway |
normal function: concentration of p53 is increased in the cell in response to cell stress controls response to damage/stress mutated in >50% of cancer transcription factor tumor suppressor only 1 copy needs to be mutated dominate negative effect |
|
|
Myc pathway |
normal function: another transcription factor transcribes genes lead to cell growth/devision oncogene tumors still arise after delay not in every cell myc + ras are important drivers -more mutations needed |
|
|
Pathways leading to metastasis |
cadherins normally involved in cell-cell adhesion to adherens junctions loss of cadherin can promote both local invasiveness and metastasis potential to be tumor suppressor gene any protein involved in cell adhesion considered tumor suppressor gene |
|
|
Environmental influences that increase risk of cancer evidence: |
different countries have different incidences of types of cancers migrant populations adopt pattern of cancer incidence in host country |
|
|
Treatment of cancer |
surgery radiation and chemotherapy |
|
|
radiation and chemotherapy |
exploit genetic instability of cancer cells-damage DNA normal cells- still have checkpoints cancer cells just push on through so messed up it dies |
|
|
New cancer drugs |
specifically target, Brca1 and Brca2 proteins involved in repair of DNA double strand breaks, cancer cells still have single-strand break repair through enzyme PARP drug that inhibits PARP -cancer cells (BRCA deficient)- same as radiation normal cells still have BRCA so still able to repair |
|
|
successes of PARP inhibitor drugs, imatinib and antibody therapies highlight an important principle |
when we understand the genetics and subsequent cell biology, then we can design targeted methods |
