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. 2012 Sep 20;17(4):646–669. doi: 10.2478/s11658-012-0032-5

Puma, a critical mediator of cell death — one decade on from its discovery

Paweł Hikisz 1, Zofia M Kiliańska 2,✉
PMCID: PMC6275950  PMID: 23001513

Abstract

PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

Key words: Apoptosis, BH3-only proteins, Carcinogenesis, Inhibitory members of the Bcl-2 family, Intrinsic apoptosis pathway, p53, Pro-apoptotic members of Bcl-2 family, PUMA, Post-translational regulation, Transcription factors

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Abbreviations used

ADI/II

activation domain I/II

Apaf-1

apoptosis protease activating factor-1

Bad

Bcl-2 associated death promoter

Bak

Bcl-2 antagonist killer

Bax

Bcl-2 associated protein x

Bcl-2

B-cell leukemia/lymphoma-2

BH1-4

Bcl-2 homology domains 1-4

Bid

BH3 interacting domain death agonist

Bik

Bcl-2 interacting killer

Bim

Bcl-2 interacting mediator of cell death

Bmf

Bcl-2 modifying factor

Bod

Bcl-2-related ovarian death gene

Bok

Bcl-2 ovarian killer

BS1/2

p53 binding site 1/2

CHOP

C/EBP homologous protein

DEN

diethylnitrosamine

GSK-3

glycogen synthase kinase-3

HRK

harakiri, activator of apoptosis

HSPCs

hematopoietic stem/progenitor cells

HSV-1

human herpes virus

IKK

IκB kinase

IL-3

interleukin 3

Lys

lysine

Mcl-1

myeloid cell leukemia-1

MEFs

mouse embryo fibroblasts

miRNA/miR

microRNA

MLS

mitochondrial localization signal

MOMP

mitochondrial outer membrane permeabilization

NOXA (PMAP1)

phorbol-12-myristate-13-acetate-induced protein 1

OMM

outer mitochondrial membrane

PCD

programmed cell death

PI3K

phosphoinositide 3-kinase

PUMA

p53 upregulated modulator of apoptosis

ROS

reactive oxygen species

Ser

serine

Smac/DIABLO

second mitochondria-derived activator or caspases/direct IAP binding protein with low pI

TRB3

tribbles 3 homolog

UV-γIR

ultraviolet-gamma irradiation

Footnotes

The authors made an equal contribution to this paper

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