Encyclopedia of Physical Science and Technology 3rd ed - Molecular Biology (AP) WW.pdf - Fizyka - koloidalnyy

Table of Contents

(Subject Area: Molecular Biology)

Article

Authors

Pages in the Encyclopedia

Cell Death (Apoptosis)

Masato Enari

Pages 541-554

Chromatin Structure and

Modification

Fyodor D. Urnov and

Alan P. Wolffe

Pages 809-829

DNA Testing in Forensic

Science

Moses S. Schanfield

Pages 589-602

Gene Expression, Regulation

Göran Akusjärvi

Pages 501-516

Immunology-Autoimmunity

K. Michael Pollard and

Eng M. Tan

Pages 679-691

Ribozymes

Alessandra Poggi and

John J. Rossi

Pages 253-261

Translation of RNA to Protein

R. A. Cox and H. R. V.

Arnstein

Pages 31-51

Cell Death(Apoptosis)

Masato Enari

Imperial College School of Medicine at St. Mary’s

I. Overview

II. Death Factors and Their Receptors

III. Apoptotic Proteases, Caspases

IV. Signal Transduction of Death

Factor-Mediated Apoptosis

V. Cell-Free System in Apoptosis

VI. Apoptotic DNase, CAD and Its Inhibitor, ICAD

VII. Molecular Mechanism of CAD and ICAD

VIII. Physiological DNA Fragmentation and

Phagocytosis of Apoptotic Cells

IX. Perspectives

GLOSSARY

cells expressing their corresponding receptors or to at-

tenuate killing activity.

DNases Enzymes possessing DNA-cleaving activity.

Some DNases participate in chromosomal DNA degra-

dation during apoptosis.

DNA fragmentation Chromosomal DNA from apoptotic

cells gives rise to a ladder pattern on agarose gels, due

to multimeric nucleosomal units (

Apoptosis The typical process in physiological cell death

that is accompanied by nuclear and cytoplasmic con-

densation, fragmentation of cell bodies, chromosomal

DNA fragmentation, loss of mitochondrial function,

and alterations of cell membrane composition. It is

distinct in these regards from necrosis. The term was

created by Wyllie and Kerr.

Caspases Cysteine proteases, some of which are acti-

vated during apoptosis. Some caspases are involved

in processing of cytokines.

Cell-free system A biochemical technique to be recon-

stituted cellular events as in vitro reaction.

Death factors Proteins belonging to the tumor necrosis

factor (TNF) superfamily that occur on the cell sur-

faces as membrane-bound factors and in the extracel-

lular compartment as soluble factors. They kill target

180 base pairs).

Death receptors Proteins belonging to TNF receptor

family that occur on cell surface, and mediate killing

by effector cells expressing their cognate ligands.

Intracellular signal transduction The cellular machin-

ery that mediates external signals including hor-

mones, neurotransmitters, cell growth, differentiation

and death factors, or stress to their ultimate targets.

Phagocytosis The process by which phagocytes, such as

macrophages and neutrophils, engulf useless

∼

and un-

necessary cells.

541

542

Cell Death (Apoptosis)

APOPTOSIS, or programed cell death, plays an impor-

tant role in the development of organisms and in the main-

tenance of homeostasis. The failure of apoptotic programs

causes various diseases. So far, many genes regulating

apoptosis have been identiﬁed and the molecular mecha-

nism of apoptosis is being clariﬁed. In this article, I will

discuss cell death elicited through death receptors.

and Kerr in 1972. In the necrotic process, swelling of cells

precedes their explosion and results in the release of in-

tracellular components that may be toxic to other cells.

In apoptosis, the dying cells exhibit nuclear and cytoplas-

mic condensation, fragmentation of cell bodies, chromo-

somal DNA fragmentation into nucleosomal units, loss

of mitochondrial function, and alterations of cell mem-

brane composition ( Fig. 1 ). Subsequently, apoptotic cells

are engulfed by phagocytes and neighboring cells, and are

recycled. Most cells suffering physiological cell death un-

dergo the apoptotic process and the superﬂuous or harmful

cells generated during the developmental process are re-

moved by apoptosis. For example, apoptosis occurs in tail

resorption, neuronal network formation, clonal deletion of

I. OVERVIEW

Homeostasis in multicellular organisms is based on a bal-

ance between life and death of cells. Apoptosis was recog-

nized as a phenomenon distinct from necrosis by Wyllie

FIGURE 1 (a) Fas-induced apoptosis in lymphoid cells (WR19L cells overexpressing Fas). The cells were incubated

with 0.5 µ g/ml of an agonistic anti-Fas antibody at 37 ◦ C for 120 min and their ultrastructure was examined under

a transmission electron microscope. The electron micrograph of untreated cells is shown in the upper panel. Bars,

1 µ m. (b) Chromosomal DNA of growing cells (lane 1) or dying cells (lane 2) was run through a 1.5% agarose gel. M

indicates molecular weight markers.

Cell Death (Apoptosis)

543

immature and autoreactive T cells, Wolfﬁan and Mullerian

duct regression during sexual development, tumor regres-

sion, and in elimination of virus-infected cells. Further-

more, it has been suggested that apoptosis occurs in many

diseases such as cancer, fulminant hepatitis, acquired im-

mune deﬁciency syndrome (AIDS), diabetes mellitus, and

neurodegenerative disorders such as Alzheimer’s disease

and prion disease.

Growth and differentiation of cells are strictly regulated

by factors such as cytokines and low-molecular-weight

compounds such as steroid hormones. These factors are

generally bound to the corresponding receptors in order to

transduce the appropriate cell signals, to promote growth

and differentiation. On the other hand, apoptotic cell death

is aggressively controlled by a number of polypeptides,

so-called death factors exposed at the cell surface or cir-

culating in the body as soluble factors in some situations.

Growth and differentiation factors act via transcriptional

regulation through the activation of a series of protein ki-

nases. On the other hand, death factors execute apoptosis

through the activation of caspases, and many proteins es-

sential for cell survival are degraded by these activated cas-

pases. It is currently believed that apoptotic death is due to

the degradation of many functional proteins by caspases.

Cell-free systems for the study of apoptosis have been

established and facilitate our understanding of the under-

lying molecular mechanisms. Several factors involved in

apoptotic pathways have been identiﬁed and part of these

pathways has been revealed by biochemical approaches

based on cell-free apoptosis system. Regulatory mecha-

nisms for apoptosis include: the CED-3/caspase family

proteases and CED-4/Apaf-1 family which act as execu-

tors of apoptosis; CED-9/Bcl-2 family (including anti-

apoptotic and pro-apoptotic factors) which act as regu-

lators of apoptosis, and many factors which contribute

to apoptotic morphological changes have been identiﬁed.

Here, I shall focus on the currently proposed molecular

mechanisms of death receptor activity and caspase activa-

tion. Moreover, I will also discuss the DNase responsible

for apoptotic DNA fragmentation, both in vitro and in

vivo, and ﬁnally the mechanism by which apoptotic cells

are cleared.

receptor. Among these,

TNFRII, CD27, and CD30 induce the expression of both

TNF and TNFRI by their cognate ligands, and subsequent

induction of apoptosis appears to occur.

On the other hand, death factors are a member of

the TNF family and exist on the cell surface or as

soluble factors. Most death factors are synthesized as

type II-membrane proteins and subjected to shedding by

membrane-associated metalloproteinases in order to gen-

erate soluble forms of death factors. A well-established

mechanism for shedding of death factors is seen in the case

of TNF. Membrane-bound TNF (memTNF) is cleaved at

the outer cellular membrane by a membrane-spanning pro-

tease, so-called TNF

-converting enzyme (TACE), which

is a member of metalloproteinase-disintegrin (ADAM)

family. memTNF is superior to soluble TNF (sTNF) in

activating TNFRII in various cellular responses, includ-

ing T-cell proliferation, inﬂammation, and cytotoxicity.

These results imply that memTNF regulates cellular re-

sponses via restricted cell-to-cell interaction under physi-

ological conditions and that sTNF may attenuate TNFRII-

mediated responses. The shedding mechanism for other

death factors may be similar to that for TNF. Like in shed-

ding of TNF, the membrane form of Fas ligand (mem-

FasL) is also cleaved by an unknown metalloproteinase

other than TACE present on the plasma membranes. In

addition, the soluble form of Fas ligand (sFasL) inhibits

mFasL-mediated apoptosis in human peripheral blood T

lymphocytes in vitro.

It is believed that death receptors are activated by

ligand-induced trimerization, as opposed to the activa-

tion of growth factor receptors, which occurs by dimer-

ization. Most death factors, but not all, are present as

trimers. X-ray structural analyses have revealed that TNF-

, CD40L, and TRAIL are homotrimeric proteins.

Among these, TRAIL has unique characteristics. TRAIL

requires a zinc ion for biological activity and selectively

induces apoptosis in mouse tumor cells but not in nor-

mal cells. Moreover, administration of soluble TRAIL to

mice implanted with human tumors causes effective re-

duction of tumor size without any injury of normal tis-

sues. These results suggest that TRAIL may be applicable

as an anti-cancer drug. However, a recent paper reported

that TRAIL induces apoptosis in human hepatocytes,

indicating that substantial liver toxicity might result if

II. DEATH FACTORS AND

THEIR RECEPTORS

Many cells have death receptors on the surface of their

plasma membranes and apoptosis is triggered by their cog-

nate ligands. Death receptors belong to the superfamily

of tumor necrosis factor (TNF) receptors. Most consist

of a cysteine-rich extracellular domain, a membrane-

spanning domain, and a cytoplasmic domain containing

a death domain (DD) that is required for transducing

apoptotic signals to cells. Six DD-containing death re-

ceptors, namely Fas/Apo1/CD95, type I TNF recep-

tor (TNFRI), DR3/Apo3/WSL-1/TRAMP, DR4/TRAIL-

R1 (TNF-related apoptosis-inducing ligand receptor-1),

DR5/TRAIL-R2/TRICK2/KILLER and DR6 have been

identiﬁed so far. In addition, there are DD-less death re-

ceptors such as type II TNF receptor (TNFRII), CD27,

CD30, CD40, and lymphotoxin-

, TNF-

Encyclopedia of Physical Science and Technology 3rd ed - Molecular Biology (AP) WW.pdf

Plik z chomika:

Inne pliki z tego folderu:

Inne foldery tego chomika: