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Degradation and beyond: Control of androgen receptor activity by the proteasome system

Abstract

The androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.

Abbreviations

AATF:

apoptosis antagonizing factor

APIS complex:

AAA proteins independent of 20S

ARA54:

AR-associated protein 54

ARA70:

AR-associated protein 70

ARE:

androgen responsive element

ARNIP:

AR N-terminal interacting protein

bFGF:

basic fibroblast growth factor

CARM1:

coactivator-associated arginine methyltransferase 1

CHIP:

C-terminus Hsp70 interacting protein

DBD:

DNA binding domain

E6-AP:

E6-associated protein

GRIP-1:

glucocorticoid receptor interacting protein 1

GSK3β:

glycogen synthase kinase 3β

HDAC1:

histone deacetylase 1

HECT:

homologous to the E6-AP C-terminus

HEK293:

human embryonal kidney cell line

HepG2:

human hepatoma cell line

Hsp90:

heat shock protein 90

IGF-1:

insulin-like growth factor 1

IL-6:

interleukin 6

KLK2:

kallikrein 2

KLKK:

lysine (K), leucine (L)

LBD:

ligand binding domain

LNCaP:

lymph node carcinoma of prostate cell line

MAPK:

mitogen activated protein kinase

Mdm2:

Murine double minute 2

NcoR:

nuclear receptor corepressor

NEDD8:

neural precursor cell-expressed developmentally down-regulated

NLS:

nuclear localisation signal

p/CAF:

p300/CBP-associated factor

p300/CBP:

CREB-binding protein

PC3:

human prostate carcinoma cell line

PEST:

proline (P), glutamic acid (E), serine (S), threonine (T)

PI3K:

phosphoinositide-3 kinase

PIAS1:

protein inhibitor of activated STAT

PKA:

protein kinase A

PKC:

protein kinase C

PR:

progesterone receptor

PRMT1:

protein arginine methyltransferase 1

PROTAC:

proteolysis targeting chimeric molecule

PSA:

prostate specific antigen

PSMA7:

proteasome alpha subunit 7

P-TEFb:

positive transcription elongation factor b

PTEN:

phosphatase and tensin homolog deleted on chromosome 10

RING:

really interesting new gene

RNA Pol II:

RNA polymerase II

SCF ligase:

Skp2/cullin1/F-box

SMRT:

silencing mediator of retinoic acid and thyroid hormone receptor

SNURF:

small nuclear RING finger

SRC1:

steroid receptor coactivator 1

Sugl:

suppressor of Gal

SUMO:

small ubiquitin-like modifier

SWI/SNF:

mating type switching/sucrose non-fermenting

TBL1:

transducin-β-like

TBLR1:

transduction-β-like-related protein

TBP:

TATA binding protein

TFIIB, D, F, H:

general transcription factors

TRAP:

thyroid hormone receptor-associated protein

TSG101:

tumour susceptibility gene 101

UAC:

ubiquitin activating enzyme

UBC:

ubiquitin conjugating enzyme

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Correspondence to Tomasz Jaworski.

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Key words

  • AR
  • Degradation
  • Prostate cancer
  • Proteasome
  • Transcription
  • Ubiquitin