Apoptosis

Alberts et al., 1076, 1173-1175, 1238
Two types od cell death:
1. necrosis - from injury, cells burst, there is inflammation
2. programmed cell death = apoptosis
nuclei condense & fragment,
TRANSPARENCY (Fig. 22-35, p. 1174
cell is phagocytosed (by macrophages for instance), no inflammation
TRANSPARENCY (Fig. 21-46, p. 1146)
examples: lymphocytes eliminated, tadpole tail lost, get rid of webs between digits
in C. elegans, ced-3 and -4 (cell death abnormal [can't these guys spell?])
-131 cells which should die survive if mutant
ced-9, if normal, represses death
protein Ced-3 is a protease,
Ced 9 is like Bcl-2, product of bcl-2 proto-oncogene
(as of 1997, see Fox paper, below) the mammalian homologue of C. elegans CED-4
DNA gets chopped into 50-300 bp lengths, hence "ladder" seen in gel
(but note, this would only be seen transiently during the death)
A. Kumar, Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases, Science 278, 1997 1630-1632
TRANSPARENCY Figure 2 shows ladder
K. McCall and H. Steller, Requirement for DCP-1 caspase during Drosophila oogenesis, Science 279, 230-234, 1994
TRANSPARENCY Fig. 1, shows TUNEL (Tdt-mediated deoxyuridine triphosphate nick end labeling, of course) which stains cells which are dying of apoptosis
(like above, this would only be seen transiently during the death)

Some say the world will end in fire,
Some say in ice.
From what I've tasted of desire
I hold with those who favor fire.
But if it had to perish twice,
I think I know enough of hate
To say that for destruction ice
Is also great
And would suffice
R. Frost

M. Barinaga, Cell suicide: by ICE, not fire (Research news) Science 263, 1994, 754-756.
TRANSPARENCY a frequently shown figure of how homo- or hetero-dimers of BCL-2 and BAX determines life or death respectively
"Apoptosis" Greek word describing plant leaf shedding
C. elegans
ced-3 and ced-4 death genes
ced-3 like gene for ICE = interleukin-1 beta-converting enzyme
CED-3 is also like CPP32 (caspase) (see Fox paper below)
ICE activates interleukin 1 beta by cutting an inactive precursor protein
(ICE has 2 subunite chopped out of a 45 kDa precursor and works as tetramer of 2 of each, Umansky)
ced-9 anti-death genes = (23% identical with) bcl-2
bax blocks bcl-2

M. Barinaga, Forging a path to cell death (Research news), Science 273, 1996, 735-737
(also a quick path from membrane to nucleus, a common theme in this last part of the course)
TRANSPARENCY a figure to show how Fas-ligand and TNF signal through receptors to activate or inhibit apoptosis through proteases
note mention of nuclear factor kappa B (NF-KB), a transcription factor which regulates transcriptions of certain proteins
TNF, Tumor Necrosis Factor and recepors TNFR1 & TNFR2
TRADD = TNF receptor associated death domain protein
FADD = Fas associated death domain protein = MORT1
binds to MACH=MORT1 associated CED 3/ICE homologue
alias FLICE = FADD-like ICE
80 amino acid death domain to trigger cell death pathway

R.C.Duke et al., Cell suicide in health and disease, Scientific American, December, 1996, (Volume 275#6) 80-87 (and cover)
Cell death in heart attack and stroke is especially bad since these cells are not replaced by mitosis:
Initially, necrosis, but some apoptosis can follow
several interesting examples of tricks viruses use to inhibit the death of the cells they infect
Epstein-Barr (mononucleosis) - produce Bcl-2-like substances
Papillomavirus (cervical cancer) degrade p53
p53, missing or inactive in many tumors, activates apoptosis
Cowpox - prevents ICE-like proteases from working
An interesting cancer story:
Melanocytes (important since they block damaging light) have lots of Bcl-2, cancers are aggressive
This paper elaborates on the Fas signalling, and is very general
the discovery of ICE led to the elaboration of ICE-like proteasesCells can die because of deprivation of survival factors, Example disappearance of interleukin-2 (T-cell survival factor) at end of infection
on the other hand, there can be death signals like Fas
Infected cells display Fas - killer-T cells display Fas-ligand
TRANSPARENCY How T cells may be damaged in AIDS by apaptosis and involvement of Fas and ligand

J. L. Fox, Whodunit? The apoptosis conspiracy begins to unravel (news), J. NIH Research, 9, April 1997, 31-32
Mitochondrial membrane is important, oddly, and cytochrome c (oxidative phosphorylation), also oddly
order seems to be CED-9 -> CED-4 -> CED-3
there are conserved domains called BH2 and BH3 on CED-9 to mediate this interaction
CED-9 is on membranes like nuclear membrane while CED-4 is cytoplasmic
(26 kDa, transmembrane domane, see Umansky)
thus CED-9 could pull CED-4 away from being to activate "killer protein" CED-3

E. H.-Y. Cheng et al., Conversion of Bcl-2 to a Bax-like death effector by caspases, Science 278, 1966-1968, 1997
caspases are cysteine proteases which chop protein kinases, retinoblastoma protein, cytoskeletal proteins
Cleavage of a novel protein called DFF triggers DNA fragmentation
"cleavage of Bcl-2 by caspases unleash a latent proapoptotic activity"

S. R. Umansky, Apoptosis: molecular and cellular mechanisms (a review), Molecular biology 30 285-295, 1996

T. Hoey, A new player in cell death (Signal transduction), 1997, 1678-1579
TRANSPRENCY - (and a preview of coming attractions about JAK-STAT signalling)
quick trip from membrane to nucleus in transmembrane cytokine receptors which are not enzymes in and of themselves is mediated through help of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs)


This page was last updated on December 19, 2001

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