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Current concepts in apoptosis: The physiological suicide program revisited

Abstract

Apoptosis, or programmed cell death (PCD), involves a complex network of biochemical pathways that normally ensure a homeostatic balance between cellular proliferation and turnover in nearly all tissues. Apoptosis is essential for the body, as its deregulation can lead to several diseases. It plays a major role in a variety of physiological events, including embryonic development, tissue renewal, hormone-induced tissue atrophy, removal of inflammatory cells, and the evolution of granulation tissue into scar tissue. It also has an essential role in wound repair. The various cellular and biochemical mechanisms involved in apoptosis are not fully understood. However, there are two major pathways, the extrinsic pathway (receptor-mediated apoptotic pathway) and the intrinsic pathway (mitochondria-mediated apoptotic pathway), which are both well established. The key component in both is the activation of the caspase cascade. Caspases belong to the family of proteases that ultimately, by cleaving a set of proteins, cause disassembly of the cell. Although the caspase-mediated proteolytic cascade represents a central point in the apoptotic response, its initiation is tightly regulated by a variety of other factors. Among them, Bcl-2 family proteins, TNF and p53 play pivotal roles in the regulation of caspase activation and in the regulation of apoptosis. This review summarizes the established concepts in apoptosis as a physiological cell suicide program, highlighting the recent and significant advances in its study.

Abbreviations

Apaf-1:

apoptosis protease activating factor-1

Bcl:

B-cell lymphoma family

BH:

Bcl-2 homology

tBid:

truncated Bid

BIR:

baculoviral IAP repeat

BRUCE:

BIR repeat-containing ubiquitin-conjugating enzyme

CARD:

caspase recruitment domain

CDR:

cysteine-rich extracellular domain

DISC:

death-inducing signaling complex

DD:

death domain

DED:

death effector domain

DR:

death-inducing receptor

ER:

endoplasmic reticulum

FADD:

Fas-associated death domain protein

FLIP:

FADD-like-ICE-inhibitory protein or FLICE inhibitory protein

G1:

GAP1

IAP:

inhibitor of apoptosis

IL:

interleukin

MOMP:

mitochondrial outer membrane permeabilization

PCD:

programmed cell death

PUMA:

p53-up-regulated modulator of apoptosis

PS:

phosphatidylserine

PTP:

permeability transition pore

RIP:

receptor interacting protein

TACE:

TNF alpha-converting enzyme

TGF-β:

transforming growth factor-β

TNF-α:

tumor necrosis factor α

TNFR-1:

tumor necrosis factor receptor-1

TRAIL:

TNF-related apoptosis-inducing ligand

TRADD:

TNF-receptor associated protein with death domain

TUNEL:

terminal deoxynucleotidyl transferase-mediated (TdT-mediated) dUTP-digoxigenin nick end labeling

VDAC:

voltage-dependent anion channel

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Correspondence to Ganapathy K. Bhat.

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Chowdhury, I., Tharakan, B. & Bhat, G.K. Current concepts in apoptosis: The physiological suicide program revisited. Cell Mol Biol Lett 11, 506–525 (2006). https://doi.org/10.2478/s11658-006-0041-3

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Key words

  • Apoptosis
  • Programmed cell death
  • Pathways
  • Caspases
  • Bcl-2
  • p53
  • TNF
  • Apaf