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. 2008 Feb 29;13(3):353–365. doi: 10.2478/s11658-008-0008-7

The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research

Halina Ostrowska 1,✉
PMCID: PMC6275582  PMID: 18311545

Abstract

The ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins, including those that control cell cycle progression, apoptosis, signal transduction and the NF-κB transcriptional pathway. Aberrations in the ubiquitin-proteasome system underlie the pathogenesis of many human diseases, so both the ubiquitin-conjugating system and the 20S proteasome are important targets for drug discovery. This article presents a few of the most important examples of the small molecule inhibitors and modulators targeting the ubiquitin-proteasome system, their mode of action, and their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases.

Keywords: E3 ubiquitin ligases, Proteasome, Inhibitors, Modulators, Therapeutic potential, Cancer, Stroke, Cardiovascular diseases

Full Text

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Abbreviations used

AML

acute myeloid leukemia

ARF

acute renal failure

BMSCs

bone marrow stromal cells

βTrPC

β-transducin repeat containing protein

CDK

cyclindependent kinase

ChT-L

chymotrypsin-like

C-L

caspase-like

CLL

chronic lymphocytic leukemia

DHT

dihydroxytestosterone

DOCA

deoxycortycosterone

DUB

deubiquitinating enzyme

E1

ubiquitin-activating enzyme

E2

ubiquitin-conjugating enzyme

E3

ubiquitin-protein ligase

ET-1

endothelin-1

Hdm2

human counterpart of Mdm2

HIF-1

hypoxia inducible factor

IKK

IκB kinase

IL-1

interleukin

INF-γ

interferon gamma

LMP

low-molecular-mass polypeptide

Mdm2

murine double minute 2

Met-AP-2

metionine aminopeptidase-2

MHC

major histocompatibility complex

MM

multiple myeloma

NF-κB

nuclear factor-kappaB

pIκBα

phosphorylated inhibitor-κβ

Protacs

proteolytic targeting chimeric molecules

pVHL

phosphorylated von Hippel-Lindau tumor suppressor

RITA

reactivation of p53 and induction of tumor cell apoptosis

SCF

complex formed by Skp1, cullin and F-box protein

siRNA

small interfering RNA

SKP2

S-phase kinase associated protein 2

SMPI

small molecule proteolysis inducers

T-L

trypsin-like

TNF

tumor necrosis factor

UPS

ubiquitin-proteasome system

VCAM

various leukocyte adhesion molecules

VEGF

vascular endothelial growth factor

Footnotes

Paper authored by participants of the international conference: XXXIV Winter School of the Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Zakopane, March 7–11, 2007, “The Cell and Its Environment”. Publication cost was partially covered by the organisers of this meeting.

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