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365 Cards in this Set
- Front
- Back
Platelets are cell fragments and can’t make new anything, let alone new COX;
|
But they can USE cox and other enzymes
|
|
Reversible inhibitors are no good at:
|
decreasing risk of CVD
|
|
Rb-EF2 complex =
|
transcriptional *repressor*
- deacetylates histones, keeping S-phase genes from being expressed |
|
Retinoblastoma = eye tumor;
(3) |
1. aggressive - needs early diagnosis
2. familial inheritance is most common form of contraction 3. ~ two-hit hypothesis |
|
sproadic RB is NOT
|
familial;
rather, a rare inactivation of both alleles |
|
tumor suppressor =
|
inhibitor of cell cycle progression = brakes
e.g. Rb |
|
mutation in a tumor suppressor =>
|
*loss* of function
|
|
proto-oncogene =
|
stimulator of cell cycle progression = acceleration
e.g. Cyclin D |
|
mutation in a proto-oncogene =>
|
oncogene => GAIN of function
|
|
Cyclin D overexpression =>
|
cancers
|
|
RB underexpression =>
|
cancers
|
|
Rule #3: a cell must not start to replicate DNA unless its mass is
|
sufficient to support the replication
~ G1 |
|
***what is cmyc?***
|
a TF for cell growth
|
|
cmyc sits on a promoter, => increase in
|
expression of protein synthesis genes
|
|
***what activates cmyc to inc.expression of protein synthesis genes?***
|
***P'n, via both sides of TKR***
|
|
overexpression of cmyc =>
|
leukemias, lymphomas
|
|
Rule #4: a cell must replicate DNA once and
|
only once during each division
|
|
***what Cyclin/Cdk combo drives replication?***
|
Cyclin E/ Cdk 2
|
|
Licensing:
(2) |
1. G1
2. helicases load onto origins of replication |
|
Firing:
(2) |
1. S phase
2. helicases, DNA polym, etc. are activated => replication => two sets of chromosomes in G2 |
|
****what does Cyclin E/Cdk 2 do at the same time during replication?****
(2) |
1. inhibits re-licensing
2. stimulates Firing |
|
mutation => re-licensing (improper) =>=>
|
broken chromosomes => cell death from lots of erros
- or tumor from a little re-licensing |
|
how do cyclins cycle?
(2) |
1. regulated induction
2. regulated destruction |
|
Ubiquitination: what do the E's do?
|
E1 activates Ub,
E2 carries it to E3, E3 targets it to specific proteins => proteosome => degradation |
|
Cullin (a type of E3) =
|
scaffold
Roc = necessary catalyst |
|
what is responsible for Cyclin E degradation?
|
**Cullin 1**
|
|
by what process is Cyclin E/Cdk2 degraded?
|
***Cyclin E/Cdk2 Phosphorylates itself***
=> Cullin binds => Ub'n => targeted to proteosome |
|
what activates Cdk's?
(2) |
1. cyclin binding
2. P'n of Cdk activation loop |
|
what inhibits Cdk's?
(3) |
1. cyclin destruction
2. de-P'n of activation loop 3. ***Cdk inhibitor binding*** |
|
***2 examples of Cdk inhibitors:***
|
p16,
p27 |
|
which Cdk's do p16's inhibit?
|
***Cdk's 4 and 6 ONLY***
|
|
in many cancers, both alleles for p16 are
|
lost
|
|
***which Cdk's do p27's inhibit?***
|
Cdk's 1 and 2***
|
|
***p16's and p27's are highly expressed in:
(3) |
quiescent, senescent, and terminally-differentiated cells
|
|
mice lacking p27 are:
|
larger
- Cyclin E/Cdk2's are *unchecked* => cancer in some tissues |
|
mice lacking Skp2 are:
|
smaller
(Skp = an E2 Ub. that carries p27) - p27 isn't degraded, continues to repress Cyclin E/Cdk2 => can't initiate S-phase as much |
|
***cancer cells typically affect only:***
|
one point of a pathway
- but they affect *two pathways* => cancer |
|
lipoprotein =
|
transport for Tg's pl's, free cholesterol, and CE
|
|
center of lipoproteins =
(2) |
CE and TG's
|
|
outside of lipoproteins =
(3) |
free cholesterol, pl's, and apoproteins
|
|
lipoproteins are classified by:
|
density;
chylomicron < VLDL < LDL <HDL |
|
density of lipoporteins:
(3) |
1, inversely related to size
2. inversely related to TG content 3. directly proportional to protein and pl content |
|
not dense =
|
very big
|
|
chylomicrons are the _____________, HDL's are the ___________
|
largest;
smallest |
|
apoA ~
(2) |
1. targets HDL to per. tissues
2. activation of LCAT |
|
apoB-100 ~
|
***binding of LDL to LDL receptors***
|
|
apoC =
|
activator of LPL
(lipoprotein lipase) |
|
apoE ~
|
binding of chylomicron/VLDL/HDL remnants to the liver
|
|
apoE + apoB-100 ~
|
binding of IDL to liver
|
|
Lipoprotein Lipase:
(3) |
1. located in endo. cells *adjacent to* peripheral tissue, especially adipose
2. *required* for removal of TG's from chylo's and VLDL 3. insulin inc. its production AND translocation |
|
Hepatic Lipase:
(3) |
1. located near liver
2. hydrolyzes TG's from chylo's and VLDL in their conversion to LDL's 3. unregulated |
|
what LPL doesn't remove,
|
hepatic lipase does
|
|
***removal of TG's =>
|
remnant particles
|
|
cholesterol can diffuse:
(2) |
1. among lipoproteins
2. between lipoproteins and tissue |
|
half-life of chylomicron =
|
minutes
- ***normally, there are NO chylomicrons in the the blood during fed state*** |
|
half-life of VLDL's =
|
days
- also a rapid process - shouldn't see VLDL in blood in fed state |
|
reverse cholesterol transport ~
|
cholesterol from peripheral tissue to liver
|
|
3 critical enzymes for reverse cholesterol transport:
|
1. LCAT
2. CETP 3. PLTP |
|
***what does LCAT do?***
|
makes free cholesterol into CE
- thereby trapping it in the lipoproteins |
|
***what does CETP do?***
|
transfers CE from HDL to:
V / I / LDL |
|
***what does PLTP do?***
|
transfers pl's and TG's from: VLDL, IDL, LDL
to: HDL |
|
apoA - 3 jobs:
|
1. target HDL to per. tissue, via apo A receptors
2. activates ABC1 3. activates LCAT |
|
what does the ABC1 transporter do?
|
increases efflux of cholesterol FROM per. tissue into HDL
|
|
HDL = repository of
|
apoproteins
|
|
Reverse Cholesterol Transport pathway:
(6) |
1. HDL made by liver and intestine, has apo A and apo E
2. HDLs pick up apoC and apoE from chylomicron/VLDL remnants 3. bind apoA receptors on per. tissues, take up cholesterol => HDL3 4. LCAT (on HDL) traps chol. as CE 5. CETP (on HDL) transfers CE to V, I, and LDL => delivery of chol. to liver 6. PLTP (on HDL) transfers TG's and pl's to HDL3 => HDL2 => internalized by liver |
|
purpose of exogenous pathway:
|
transport dietary lipids to peripheral tissue
|
|
purpose of edogenous pathway:
|
transport of lipids synthesized by the liver
|
|
purpose of reverse cholesterol pathway:
|
transport cholesterol from peripheral tissues to liver
|
|
collagen cross-links b/w and within helices =>
|
strength
|
|
fibraller collagen ~
|
bone, cartilage, tendon, skin, etc.
|
|
non-fibraller collagen ~
|
basement membrane
|
|
fibronectins:
(4) |
1. increase adhesion of cells
2. link cells to other ECM components 3. form on the surface of a cell 4. may increase or dec. cell migration via pathways |
|
***RGD =
|
fibronectin's cell-binding domain
|
|
**integrellin = structural agonist of
|
RGD;
=> blocks RGD => dec. binding capacity of platelets => disruption of blood clot formation |
|
elastin is covered by:
|
**fibrillin**
|
|
mutations in fibrillin (on top of elastin) =>
|
Marfa's Syndrome
(rupture of aorta) |
|
integrins =
|
***major cell receptors for MANY ECM proteins
- connect ECM to cell's cytoskeleton |
|
only B4 integrins ~
|
IF's/hemidesmosomes
- the rest => actin filaments |
|
**3 important integrins:
|
1. a5B1
2. B2 3. aIIbB3 |
|
a5B1 integrins only bind to
|
***RGD sequence of *fibronectin ***
|
|
B2 integrins are only found on
|
leukocytes
=> FIRM adhesion of leukocytes to endo cells |
|
a II b B3 integrins are found ONLY on
|
platelets
- bind to *fibrin* |
|
a II b B3 integrins are normally inactive, but become able to bind fibrin/fibrinogen when
|
platelets are activated
|
|
missing or mutated a II b B3 integrins =>
|
Glanzmann's
= don't form effective blood clots |
|
***a II b B3 integrins are targeted by:***
(2) |
1. integrellin
2. Reopro, an AB |
|
why target a II b B3 integrins?
|
dec. blood clots
|
|
**focal adhesion =
|
site of connection b/w integrins and ECM proteins
|
|
FAK =
|
cytosolic tyrosine kinase
|
|
when integrins engage the ECM, FAK is activated =>
|
growth, differentiation, and migration of cells
- FAK is overexpressed in some cancers |
|
Leukocyte Adhesion Deficiency =
|
leukocytes don't express B2 integrins
|
|
LAD =>
|
failure to adhere to endo cells => failure to mount inflammatory response/combat infections
|
|
normal leukocyte rolling ~
|
selectins
|
|
once B2 integrins are activated on leukocytes, leukocytes can bind to:
|
**ICAM-1** on cell surface
=> strong adhesion => leukocyte flattens => enters cells |
|
***for T-lymphocytes, what is the integrin that allows them to bind, and what do they bind to:
|
a4B1,
VCAM => strong adhesion => effect in cells |
|
Tysabri, an AB against a4B1 => blocking lymphocytes => treatment of
|
MS, Crohn's
|
|
complex carbs =
|
sugars + prot. or sugars + lipids
|
|
GAG's =
|
polymers of negative disaccharide repeats
|
|
proteoglycans =
|
GAG chains hanging off a protein
- mostly all carbohydrate |
|
glycoprotein =
|
mostly protein
|
|
4 properties of proteoglycans/GAG's:
|
1. repulsion via negative charges
2. lubricant 3. shock absorber 4. structure |
|
which components of the membrane and ECM undergo turnover?
|
**ALL of them
|
|
GAG's/proteoglycans are endocytosed, =>
|
lysosomes
|
|
defects in degradative enzymes => GAG accumulation in both:
|
lysosomes and ECM => debilitating deformities
|
|
the N-terminal AA sequence of glycoproteins targets them to
|
ER/Golgi
|
|
O-linked glycoprotein refers to:
|
the OH of Ser/Thr
|
|
N-linked glycoprotein refers to:
2 facts: |
the NH2 of Asn
1. **MOST glycoproteins are N-linked** 2. N-linked = targeted to ECM or cell surface |
|
which enzyme adds mannose-6-P to glycoproteins, for degradation?
|
phosphotransferase
|
|
if something other than mannose-6-P is attached to a glycoprotein, the glycoprotein is targeted to:
|
the cell surface or ECM
|
|
function of glycoproteins =
|
**zip codes**
=> to lysosomes, plasma, vesicles bound for ECM |
|
most glycolipids are:
|
sphingolipids
|
|
sphingosine =
|
long-chain amino alcohol
|
|
there are lots of sphingolipids in the
|
nervous system
- neurons, myelin |
|
sphingolipidosis =
|
genetic defect in sphingolipid metabolism
- not breaking down sphingolipids - a kind of lysosomal disease |
|
sphingolipidosis =>
|
MR, early death
|
|
sphingolipids are degraded in
|
lysosomes too
|
|
accumulation of sphingolipids =>
|
pathology - cells choke to death
- same is true for accumulation of GAG's, surface glycoproteins |
|
4 Sphingomyelin diseases:
|
1. Krabbe
2. MLD 3. Tay-Sachs 4. Niemann Pick A+B all ~ defects in degradation |
|
which lipids accumulate in Krabbe disease?
(2) |
1. cerebroside
2. psychosine |
|
which lipid accumulates in MLD?
(metachromatic leukodystrophy) |
sulfatide
|
|
which lipid accumulates in Tay-Sachs?
|
ganglioside
|
|
which lipid accumulates in Niemann Pick A+B?
|
sphingomyelin
|
|
sphingomyelin is found in:
|
ALL cells
|
|
where are gangliosides mostly found?
|
neurons
|
|
sulfatide =
|
sulfated cerebroside
|
|
disruption of regular turnover/catabolism =>
|
destruction of CNS myelin
|
|
AGE =>
|
neuropathy, athero, etc.
|
|
ceramide =
|
sphingosine + FA
|
|
cerebroside =
|
major myelin lipid
|
|
gangliosides ~
(2) |
big sugar heads, sialic acid
|
|
***muccopolysaccharidosis =
|
defective catabolism of GAG's
|
|
2 examples of muccopolysaccharidosis:
|
1. Hunter's syndrome
2. Hurley's syndrome |
|
effects of mineralcorticoids =
(3) |
1. inc. blood pressure
2. inc. blood volume 3. inc. vasoconstriction |
|
how do mineralcorticoids achieve their effects? via:
(2) |
1. inc. retention of Na+ and H2O
2. inc. excretion of K+ and H+ |
|
effects of glucocorticoids =
(2) |
1. inc. fuel
2. dec. immune response |
|
androgens and estrogens increase
|
male and female sex characteristics, respectively
|
|
***ACE inhibitors =>
|
**dec. in BP**
|
|
**what inhibits aldosterone production?**
|
cGMP
|
|
how are lipids transported through the blood?
|
BOUND to vehicles
|
|
how many Zn2+ binding fingers do steroid hormones have?
|
2
|
|
the 1st finger of steroid hormones controls:
|
DNA binding
|
|
the 2nd finger of steroid hormones controls:
|
dimerization of hormone receptor
|
|
HRE = hormone response element =
|
**promoter** of hormone-responsive genes
|
|
HRE's are:
|
inverted or direct repeats of 2 "half sites"
|
|
a hormone receptor's specificity for binding to a particular gene depends on:
(2) |
1. the orientation of the repeats
2. spacing between the repeats |
|
***what kind of HRE's do homodimer receptors bind to?***
|
***inverted-repeat HRE's***
|
|
***what kind of HRE's do heterodimeric receptors bind to?***
|
**direct-repeat HRE's**
|
|
how does a free hormone enter the cell?
|
by diffusion
|
|
what binds HRE?
|
the hormone-receptor complex
|
|
what are the 2 classes of steroid hormones, in terms of binding location?
|
1. cytoplasmic class
2. nuclear class |
|
cytoplasmic class hormones bind the receptor in:
|
the cytosplasm first
=> dissociate from heat-shock proteins => go to nucleus |
|
which steroids belong in the cytoplasmic class?
|
MC's,
GC's |
|
steroids in the nuclear class bind to their receptor only in:
|
the nucleus
- Androgens, Estrogens, Progesterone |
|
steroid hormones only regulate:
|
transcription
|
|
3 known targets of cortisol:
|
1. pyruvate carboxylase => GNG
2. glucose-6-phosphatase => glucose release 3. transaminase |
|
GC's inhibit expression of:
(2) |
1. cytokine genes (~activation of immune cells)
2. adhesion genes (~draw immune cells to inflammation ) |
|
GC's inhibit immune response via
|
increased expression of inhibitors
|
|
congenital adrenal hyperplasia (CAH) =
|
disruption of adrenal steroid secretion via defect in enzymes
|
|
95% of CAH cases involve a defect in:
|
21a-hydroxylase
|
|
5% of CAH cases involve a defect in:
|
11B-hydroxylase
|
|
which enzymes, if lost, has the most devastating effects on steroid hormones?
|
3B-ol-DH
|
|
***defects in 21a or 11B-hydroxylase have NO effects on:***
|
gonadal steroids
|
|
***dec. in MC's and GC's =>
|
accumulation of intermediates => inc. in DHEA => male sex characteristics
|
|
DHEA =
|
Androgen
|
|
****which enzymes directly measures amount of corticosteroids?****
|
17-OHCS
|
|
****which enzyme directly measures amount of gonadal hormones?***
|
17-KS
|
|
G-actin =
|
free actin
|
|
G-actin has **ATPase activity**. hydrolysis occurs:
|
randomly*
|
|
F-actin =
|
filament-string actin
|
|
***where does attachment of G-actin onto F-actin occur?***
|
at the **barbed end**
|
|
old actin =
|
ADP-bound actin
|
|
young actin =
|
ATP-bound actin
|
|
some proteins bind preferentially to either
|
old or new actin
|
|
regulation of actin involves a number of proteins:
(4) |
1. Arp 2/3
2. cofilin 3. phalloides 4. cytochalasin |
|
***Arp2/3 complex =>
|
polymerization of actin via branching
(binds to sides and pointed ends) |
|
cofilin on actin =>
|
depolymerization of actin
|
|
cofilin preferentially binds to:
|
ADP-actin
|
|
phalloides of mushrooms =>
|
depolym
|
|
phalloides binds along
|
length and on pointed ends of actin
|
|
cytochalasin =>
|
depolymerization
|
|
cytochalasin binds at the
|
barbed ends of actin filaments
|
|
filamin =
|
dimerized cross-linker of actin
|
|
filamin =>
|
networks and bundles
|
|
severing of actin network =>
|
reorganization
|
|
what does gelsolin do to actin?
|
**severs** actin filaments in response to increased ic Ca2+
|
|
cell extension occurs via
|
actin
|
|
thin filament =
|
actin
|
|
in muscle, actin is anchored at the
|
barbed ends, to the Z-line
|
|
Myosin II is found in:
|
ALL muscle,
as well as some non-muscle tissue |
|
LMM =>
(1) |
forming filaments
|
|
HMM =>
(2) |
binding actin,
hydrolyzing ATP for contraction |
|
stimulus => Ca2+ from SR => floods muscle =>
|
binds troponin complex => movement of tropomyosin => myosin heads bind actin
|
|
myosin II in non-muscle: P'n of light chain =>
|
loop formation
|
|
Rho-GTP function =
|
activates Arp2/3
|
|
Rho ~
|
Ras superfamily
|
|
Cdc42 => WASP =>
|
ARP2/3 => polymerization
|
|
defect in WASP => dec. WASP in:
|
leukocytes
=> leukocytes migrate poorly => infection |
|
what does RhoA activate?
|
1. stress fibers
2. focal adhesions |
|
what does Rac 1 activate?
|
lamellipodia
|
|
what does Cdc42 activate?
|
filopodia
|
|
3 phases of cell migration =
|
1. extension (via actin polym.)
2. adhesion (integrins) 3. contraction (myosin via Rho) |
|
actin in non-muscle cells:
(2) |
1. G-actin reservoir
2. F-actin in networks or bundles |
|
F-actin bundles are either:
|
contractile (e.g. contractile ring)
or non-contractile (e.g.microvilli) |
|
in contractile bundles, pointed ends point in
|
opposite directions
|
|
in tight parallel F-actin bundles, pointed ends all run:
|
in the same direction
|
|
the type of actin bundle made depends on the
|
cross-linking proteins
- more space = looser = e.g. myosin binds |
|
filopodia =
|
exploratory organelles
|
|
WBC filopodia ~
|
first contact with bacteria
|
|
circumferential belt =
|
type of contractile bundle near apical surface of epithelial cells
|
|
stress fibers:
(4) |
1. rare in most cells
2. responsible for scar contracture 3. function = close wounds 4, disassembled in cancer cells, mitosis |
|
scar contracture =
|
tightening of the skin after a serious burn
|
|
4 kinds of cytoskeletal diseases:
|
1. spherocytosis
2. elliptocytosis 3. DMD 4. Usher's |
|
spherocytosis =
|
mutation in ankyrin => abnormal cell shape => hemolysis
|
|
elliptocytosis =
|
mutation in spectrin => abnormal cell shape => hemolysis
|
|
DMD =
|
mutation in dystrophin => progressive death of skeletal muscle
|
|
Usher's syndrome =
|
defect in myosin 7 => blindness/deafness
|
|
locations of MT's:
|
1. cilia/flagella (movement of fluid/sperm)
2. cytoplasm (movement of organelles) 3. mitosis (movement of chromosomes) |
|
each MT subunit consists of
|
13 monomer rows
|
|
dynein ~
|
MT movement
|
|
dynein + no crosslinks b/w MT's =>
|
MT sliding
|
|
dynein + crosslinks =>
|
MT bending
|
|
basal body =
|
9 + 2 arrangement, found in cilia/flagella
|
|
cilia = movement organs as well as:
|
sensory organs
|
|
primary cilium sticks out => fluid =>
|
bends cilium => signal sent
|
|
2 disease of cilia:
|
1. polycystic kidney disease
2. Kartagener's syndrome |
|
Kartagener's syndrome =
|
paralyzed cilia and flagella
=> inc. respiratory infections, male sterility |
|
MT doublet ~
|
cilia
|
|
MT triplet ~
|
centriole
|
|
where does addition and removal of MT subunits occur?
|
**at the positive end**
- the negative end is anchored to the centrosome |
|
MT subunits are stable when they are:
|
GTP-bound
|
|
hydrolysis of GTP cap off of MT subunits =>
|
catastrophe
|
|
what does taxol do?
|
prevent MT depolymerization
|
|
cell checkpoints make sure that the previous phase has been:
|
completed correctly
|
|
checkpoint proteins are NOT
|
involved in the cycle phase, but monitor it
|
|
loss of checkpoint =>
|
genetic instability
|
|
P'n of Y15 of Cdk's =>
|
INactivation
|
|
which protein P's Y15 of Cdk's?
|
Wee1
|
|
which protein de-P's Cdk's?
|
**Cdc25**
=> activation of Cdk's |
|
each cell must receive a complete:
|
set of replicated DNA
|
|
what holds sister chromatids together?
|
**cohesin**
|
|
how does the cell get rid of cohesin so that the chromatids can split?
|
**separase** (via APC activation)
|
|
if DNA is damaged, the cell must repair it before:
|
division
|
|
in absence of damage, p53 is kept at:
|
low levels
|
|
what keeps p53 at regular low levels?
|
Mdm2
- an **E3 ubiquinating** protein |
|
DNA damage => P'n of p53 =>
|
Mdm2 dissociates => p53 free to activate p21
=> inhibition of Cdk's |
|
***p53 is activated by:***
|
almost any cell stress or damage
|
|
high p53 (as with DNA damage) =>
|
arrest, repair, apoptosis, senescence
|
|
stress environment => increase in
|
ARF => inhibition of Mdm2 => increased p53 => inhibition of cell cylce
|
|
DNA tumor viruses are normally:
|
non-integrative
|
|
is a tumor virus' genome were to accidentally integrate into the host genome,
|
the viral genome would be constitutively expressed
|
|
viral genome constitutively expressed =>
|
E7 and E6 proteins made
|
|
HPV's E7 protein binds to:
|
Rb => pulls it off E2F => S-phase genes expressed
|
|
HPV's E6 protein binds to:
|
p53 => degradation of p53 => cell cycle continues unabated
|
|
(normally, E7 and E6 are destroyed, but not if
|
the viral genome has integrated
|
|
polynoma virus =
|
exactly like HPV, except uses Tag protein rather than E7/E6
|
|
vaccine against the polynoma virus =
|
Gardasil
|
|
Gardasil is given to younger people because:
|
HPV cancer is dormant for many years, despite being infected via sexual activity
|
|
**sporadic cancers always lose:**
|
two critical **tumor suppressor pathways**
|
|
****p16 and ARF are encoded on:****
|
***the same locus***
- mutation in one => mutation in the other |
|
the p16/ARF locus is frequently mutated in cancers =>>
|
automatic two hits
|
|
mutation of p16/ARF locus can be
|
inherited
|
|
Li-Frauman disease =
|
cancer e/w
|
|
most cancers arise:
|
spontaneously, in somatic cells
- NOT inherited |
|
almost all cancers have a non-overlapping alteration in the:
|
ARF - Mdm2 - p53 pathway
|
|
nutlins bind Mdm2, compete for
|
p53
- to stop p53 in cancer cells |
|
MT's are highly
|
dynamic
|
|
dynamic instability of MT's, 4 stages:
|
assembly => catastrophe => disassembly => rescue
|
|
which end of MT's is anchored to the centrosome?
|
the negative end
|
|
MT's are stabilized by the addition of which 2 proteins?
|
1. MAP's (MT-Associated Proteins)
2. Tau |
|
Tau ~
|
Alzheimer's
|
|
**major function of MT's =
|
transport of intracellular storage
|
|
***2 kinds of MT transport proteins**
|
1. dynein
2. kinesin |
|
dynein moves stuff to:
|
the minus end
|
|
kinesins move stuff to
|
the + end
(some exceptions) |
|
dendritic MT's ~ non-uniform poloarity
|
+'s face opposite sides
|
|
what does the drug colchicine do?
|
blocks MT polymerization by blocking tubulin
|
|
Interphase ~
|
centrosome duplicated
|
|
anaphase A and MT's:
(2) |
1. kinetochore MT's shorten
2. dynein moves chromosomes toward poles |
|
anaphsae B and MT's:
|
check
|
|
anaphase and MT's:
|
spindles get shorter as chromatids are pulled father apart, while poles move in opposite directions
|
|
prophase and MT's:
|
mitotic spindles assemble
|
|
prometaphase and MT's:
|
spindles attach to kinetochores
|
|
metaphase and MT's:
|
spindles run the length of kinetochore to centrosome
|
|
telophase and MT's:
|
contractile ring forms
|
|
contractile ring =
|
actin + myosin
|
|
Intermediate Filaments:
(3) |
1. ***no motoer proteins = no movement***
2. no polarity => low solubility 3. basic unit = tetramer |
|
function of intermediate flimanets =
|
mechanical strength/structure
|
|
animals with soft bodies have lots of
|
intermediate filaments
|
|
8 tetramers form a rope-like sturcture; cross-section =
|
32 monomers
|
|
cytokeratins also called:
|
keratins or tonofilaments
|
|
keratin is present in:
|
ALL epithelial cells
|
|
keratins are made up of paired subunits:
|
1 acidic,
1 neutral or basic |
|
keratins attach to:
(2) |
1. desmosomes
2. hemidesmosomes |
|
***mutated keratin =>
|
blistering/skin rips off
= epidermolysis bullosa simplex (EBS) |
|
2 other examples of intermediate filaments:
|
1. neurofilaments
2. vimentin |
|
vimentin is cross-linked to MT:
(2) |
1. depends on MT's for its own structure
2. will collapse when MT's disassemble |
|
nucleus transport: anything greater than _______ requires transport through __________
|
50 kDa;
nuclear pores |
|
**everything that goes to the nucleus requires:
|
NLS
|
|
***which Ras-family GTP-binding protein regulates nuclear entry?***
|
**Ran**
|
|
what are the 3 major kinds of nuclear lamina?
|
A, B, C
|
|
***P'n of nuclear lamins =>
|
**breakdown of nuclear envelope**
|
|
***Hutchinson-Gilford Progeria =
|
***mutation in gene for lamin A***
=> premature ageing |
|
cancer and an 18-wheeler:
|
you need a lot of wheels to come off before things get serious
|
|
****p53 is altered in:
|
***every cancer***
- it's not sufficient, but it's necessary for cancer |
|
cause of most cancer is NOT
|
infection
- but mutation from the inside |
|
4 different ways of achieving cancer:
|
1. genetic instability
2. abnormal proliferation 3. changes in adhesion/migration of cells 3. induction of new blood vessels (angiogenesis) |
|
Ras => MAPK, and PI3K, =>
|
increase in proliferation via Cyclin D and c-myc
|
|
mutated Ras in a constitutively active state =>
|
abnormal proliferation
|
|
constitutive action of all the parts of the TKR pathway, whether through increased expressions or increased activity, =>
|
cancers
|
|
Mdm2 ~
|
checkpoint
|
|
reciprocal translocation in CML =>
|
BRC-ABL = novel oncogene, the Philly
|
|
fusion of BCR-ABL disrupts normal auto-inhibitory domain of ABL =>
|
constitutively-active kinase (ABL) => activation of many parts of TRK pathway => abnormal proliferation of cells => CML
|
|
Which drug targets the Philly chromosome specifically?
|
Gleevec
|
|
point mutations => resistance => Gleevec ineffective =>
|
relapse
==> another specific drug against new mutations, => remission |
|
loss of Cdk control =>
|
abnormal proliferation
|
|
stimulation of VEGFR =>
|
angiogenesis
|
|
VEGFR =
|
vascular endothelial growth factor receptor
|
|
cancer occurs later in life b/c
|
mutations need to accumulate past the "break point"
|
|
inc. in heterogeneity of cancer cells => inc risk that you'll have:
|
a cell resistant to chemo
=> relapse |
|
chemotherapy induces
|
apoptosis
|
|
EVERY cell in every *multicellular* organism has
|
apoptosis
|
|
6 features of apoptosis:
|
1. cell shrinks
2. organelles preserved 3. membrane blebs 4. chromatin condenses 5. DNA fragments 6. dying cells get phagocytosed |
|
3 features of Necrosis:
|
1. cell shrinks
2. organelles break 3. *major* inflammation |
|
apoptosis requires:
|
ATP,
and sometimes proteins synthesis |
|
***apoptosis DOES occur in neurons;
|
we make twice as many neurons as we need during development
- we lose half of them as development progresses - apoptosis is turned off after development ends |
|
too much apoptosis =>
(3) |
1. stroke, SC injury
2. neurodegenerative diseases 3. AIDS |
|
too little apoptosis =>
(2) |
1. cancer
2. autoimmune disease (T-cells aren't eliminated) |
|
Ced's ~
|
C. elegans apoptosis
|
|
Extrinsic/Death Receptor Pathway: immune cells =>
|
Fas L TNF => FLTNFR => recruits Caspase 8 => cleaves Caspase 3 => activation => apoptosis
|
|
***what's the quickest pathway to apoptosis?***
|
the extrinsic pathway
|
|
Intrinsic Pathway
|
BCL-2 family proteins regulate Cytochrome C => binds to Apaf-1 => bind to Caspase 9 => activation of Caspase 3 => apoptosis
|
|
in a healthy cell, Cytochrome C is necessary for
|
energy production
|
|
what do Bcl's do?
|
punch holes in the mit, allow Cytochrome C's to leave
|
|
|
|
|
what's the key trigger/committed step of the intrinsic pathway?
|
Cytochrome C release
|
|
**p53 can induce cell death by becoming active and
|
increasing the transcription of apoptotic proteins
|
|
***viruses can stop apoptosis of infected cells via:***
|
IAP's
(Inhibitors of Apoptotic Proteins) |
|
to inhibit IAP's so that apoptosis can continue, the mit releases:
|
smac
|
|
caspase inhibitors can provide
|
neuroprotection from caspases
|
|
problem with giving caspase inhibitors for a long time:
|
may develop cancer
|
|
EM: the darker mit are being:
|
autophagocytosed
|
|
EM: Smooth ER is always near:
|
the glycogen rosettes
|
|
EM: multi-vesicular bodies =
|
late endosomes
|
|
EM: classic peroxisome =
|
medium gray with darker gray inside
|
|
EM: polysomes =
|
circular mRNA with ribosomes
|
|
Rhabdomyolysis =
|
destruction of skeletal muscle
=> myoglobin in the urine |
|
Ketone formation is regulated by _____________, not _____________
|
mass action;
hormones |
|
FA synthesis requires
|
NADPH
|
|
Platelets do NOT have a:
|
nucleus,
and just about no protein synthesis ability - ***but they do have enzymes like COX*** |
|
Phalloidin stabilizes:
|
F-actin
|
|
Krebs is located in the:
|
***mit. matrix***
|
|
Beta-2 integrins ~
|
inflammation
|
|
proteins destined for the ECM are
|
made on RER
|
|
what activates the light chain kinase of nonmuscle myosin?
|
calcium
|
|
genome instability ~
|
new mutations acquired much more rapidly
|
|
when insulin’s not around, proteolysis occurs => AA’s for GNG
- but are those AA's used by the skeletal muscle itself? |
yes.
|
|
PPaRalpha =
|
a TF
- so is PPaRy |
|
malonyl CoA inhibits
|
CPT-1
|
|
FFA's contribute to insulin resistance in liver and muscle because they:
|
block the TKR cascade.
- MAPK and PKB not stimulated as they should be => dec. in their effects (see Sheet) |
|
Cyclin D is the only cyclin that responds to:
|
extracellular GF's
|
|
cholesterol is synthesized from HMG CoA in the
|
cytosol
(80% in the liver) |
|
the S phase releases ___________ to drive cycle from G1 to S phase
|
active Cdk2
|
|
P'd p53's =
|
Mdm2 NOT attached => high p53
|
|
inc Mdm2 = dec. p53 =
|
dec tumor suppression
|
|
***c-myc =
|
TF for cell growth => proliferation
- stimulated byTKR pathways |
|
constitutively-active Ras => over-activity of:
|
c-myc and Cyclin D
|