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

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.

Abbreviations

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

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Correspondence to Halina Ostrowska.

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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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Ostrowska, H. The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research. Cell Mol Biol Lett 13, 353–365 (2008). https://doi.org/10.2478/s11658-008-0008-7

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Keywords

  • E3 ubiquitin ligases
  • Proteasome
  • Inhibitors
  • Modulators
  • Therapeutic potential
  • Cancer
  • Stroke
  • Cardiovascular diseases