Apoptosis

Question 1

Apoptosis general

Answer 1

Genetically regulated process to eliminate unwanted cells without inflamm response via budding

Question 2

Changes via apoptosis

Answer 2

Phosphatidyl serine translocated from cytoplasmic leaflet to extracell signaling phag. Membrane blebbing as cell contents not released enabling little inflammation. loss of substrate attachment, rounded phenotype. decrease in cell volume. depol of mito membrane. activation of caspases (cysteine proteases). endonuclease activation leading to DNA and RNA degradation. Chromatin condensation forming crescent bodies.

Question 3

Extrinisc apop pathway

Answer 3

Initiated by binding of death inducing ligand to a cys-rich repeat region in extracell domain of a death receptor. Death receptors such as FasR and TNF-R are integral membrane proteins with receptor domains exposed at surface of cell. Binding of complementary death activator (FasL and TNF-alpha) transmits signal to cytoplasm leading to activation of caspase 8. Initiates a cascade of caspases leading to cell death.

Question 4

E apop pathway gen

Answer 4

FasL/TNFalpha to Trimeric receptor to FADD aggregation leading to caspase 8 activation which activates Caspase 3,6,7 leading to apop via cleavage and digestion of cell proteins

Question 5

Intrinsic Apop pathway gen

Answer 5

Triggered in response to p53 activation and DNA dmg. Mito responsable for triggering pathway via cytochrome C

Question 6

I apop pathway proper

Answer 6

Cyt-C released from mito upon MPTP opening, SMAC/Diablo also leak out = inhibitors of apop inhibs (IAPs = inhib effector caspases). Cyt-C binds Apaf-1 (apoptosis protease activating factor 1) which oligomerizes into apoptosome (CARD domains join). Apoptosome = adaptor for procaspase 9 = initiator caspase. Procaspase 9 aggregates activating and initiating zymogen caspase cascade (3,6,7)

Question 7

Caspases

Answer 7

Cysteine proteases synth as zymogens. Intiators = 8,9 and effectors = 3,6,7

Question 8

CAD endonuclease

Answer 8

Apoptosis activates caspase induced DNAse (CAD) endonuclease. Cystolic CAD is activated by caspase 3 which cleaves CAD’s inhib protein. Allows CAD to enter nucleus and break DNA. Also causes chromo condensation.

Question 9

Bcl-2 Fam general

Answer 9

Anti-apop = bcl-2 and bcl-XL
Pro-apop = bax, bak, bad, bid

Question 10

BCL-2 fam info

Answer 10

bcl-2 and bcl-xl block release of cyt-c and SMAC/Diablo (Bax and Bak induce release) = prevent pore formation.
Bid links extrinsic and intrinsic paths

Question 11

IAPs

Answer 11

Block apoptosis by inhibiting effector caspases

Include: IAP-1, XIAP, Survivin

Question 12

p53 and apoptosis

Answer 12

p53 transC proapop genes (bax, bak, bid, bad) and inhibit anti apop (bcl2,XL). p53 can bind to bax:baclXL inactive complex to release bax leading to homodimerize inducing channels in mitochondria leading to apop.

Question 13

Mimics of bad and bid

Answer 13

SAHB (BH3) which induces cyt-c pathway intrinsic

Question 14

PI3K signal

Answer 14

Anti-apop

RTK to PI3K induces pip2 to pip3 leading to PKB/AKT which phos BAD and releases bcl-2

Question 15

BAD

Answer 15

normally sequesters bcl-2 and prevents it from inhib apop

Question 16

PKB

Answer 16

also stabilizes mdm2 therefore inhib p53

Question 17

PKB/AKT

Answer 17

Increase cell growth via glucose uptake and acetyl-coa prod (G1 and G2)

Question 18

Mitochondria in cancer cells

Answer 18

Abnormal activation of PI3K/AKT path leads to warburg effect showing increased glucose and therefore lactic acid build up (invasive to surrouding cells) seen in PET scans

Question 19

IKK and NFKB

Answer 19

promote cell survival
NFKB regulates apoptosis (overactive in multiple myeloma) and is a TF. Normally sequestered by IKB, IKB phos by IKK leads to IKB ubiq therefore releasing active NFKB which transC cIAPs, bcl-2, bcl-xL = survival and growth