Engineering, 2012, 5, 192-193
doi:10.4236/eng.2012.410B050 Published Online October 2012 (
Copyright © 2012 SciRes. ENG
The COP9 Signalosome Controls Adipocyte Differentiation by
Regulating CHOP Protein Stability
Xiaohua Huang, Wolfgang D u b ie l
Department of General, Visceral, Vascular and Thoracic Surgery, Division of Molecular Biology,
Charité - Universitätsmedizin Berlin, Berlin, Germany
Received 2012
Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obes-
ity. Therefore her e we investigate the role of the COP9 signalosome and of CHOP in the differentiation of LiSa-2 preadipocytes.
Keywords: COP9 Signalosome; CHOP; Adipogenesis; Cullin-RING Ubiquitin Ligase
1. Introduction
Adipogenesis (differentiation of adipocytes) is a highly com-
plex mechanism, closely cross-linked to the induction of an-
giogenesis which in turn promotes preadipocyte differentiation.
Dysfunction of adipogenesis causes obesity. The process of
adipogenesis is regulated by an elaborate network of transcrip-
tion factors that coordinate the expression of hundreds of pro-
teins responsible for establishing fat cell phenotype. In the cen-
tre of that network are the two master regulators of adipocyte
differentiation, the peroxisome proliferator-activated receptor γ
(PPAR-γ) and CCAAT/enhancer binding protein α (C/EBPα).
Besides P PAR-γ, C/EBPα is considered a primary transcription
factor that mediates adipogenesis. Early in the differentiation
program C/EBPβ is expressed, which is the transcriptional ac-
tivator of PPAR-γ and C/EBPα. Its activity is delayed by the
C/EBP homologous protein (CHOP, also called growth ar-
rest-DNA damage-induced 153, GADD153), a dominant nega-
tive form of C/EBP family members. CHOP dimerizes with
adipogenic C/EBPs, suppresses their transactivation activity
and, therefore, blocks adipogenesis. CHOP has to be
down-regulated for the progression of the differentiation pro-
gram. Interestingly, CHOP protein is degraded by the ubiquitin
(Ub) proteasome system (UPS) and proteasome inhibitors sta-
bilize the protein and block adipocyte differentiation [1].
2. Results
he COP9 signalosome (CSN) was first discovered in 1994 as
a protein complex which negatively regulates photomorpho-
genesis in Arabidopsis [2]. It consists of 8 subunits (CSN1-8;
depending on their size) and was detected in all eukaryoti c cells .
The CSN exhibits an extensive range of biological responses
including embryonic development, cell cycle, signal transduc-
tion, apoptosis, DNA repair, homeostasis and also angiogenesis
- all together reflecting the multifunctionality of the complex.
The most important function of the CSN is the regulation of the
activity of cullin-RING E3 Ub-ligases (CRLs) [3]. These li-
gases are the prominent transducers for protein degradation
mediating the formation of a complex composed of the Ub
carrying E2 conjugating enzyme and the substrate which is to
be ubiquitinated. The CSN5 subunit of the CSN exhibits a met-
alloprotease activity, which can remove Nedd8 from CRLs,
which regulates their activity [4].
Recently we have shown that the CSN is involved in adipo-
genesis [5]. Inhibitors of CSN associated kinases such curcu-
min and curcumin-like substances block the production of
VEGF in tumor cells [6] as well as in adipocytes [5]. Inhibition
of adipocyte VEGF production is one explanation for the fact
that obesity can be downregulated by curcumin and resveratrol
[7], although t he exact mechanism remained obscure.
Here we show that the curcumin-like compound piceatannol
induces CHOP in LiSa-2 preadipocytes, which blocks the
process of adipocyte differentiation. CHOP is targeted for de-
gradation via UPS by the CSN and permanent downregulation
of the CSN in LiSa-2 cells inhibits adipogenesis by stabilizing
CHOP . Permanent overexpres sion of Flag-CHOP causes a sim-
ilar phenotype as downregulation of the CSN. The CRL re-
sponsible for CHOP Ubiquitination was identified.
3. Conclusions
CHOP is an important regulator of adipogenesis. The COP9
signalosome is essential for the differentiation of adipocytes.
[1] Li, X. et al. (2006) Lactacystin inhib its 3T3 -L1 adipocyte differ-
entiation through induction of CHOP-10 expression. Biochem.
Biophys. Res. Commun. 350, 1-6.
[2] Wei, N., Chamovitz, D.A. and Deng, X.W. (1994) Arabidopsis
COP9 is a component of a novel signaling complex mediating
light control of development. Cell 78, 117 -124.
[3] Deshaies, R.J. and Joazeiro, C.A. (2009) RING domain E3 ubiq-
uitin ligas es. Annu. R ev. Biochem. 78, 399-434.
[4] Cope, G.A., Suh, G.S., Aravind, L., Schwarz, S.E., Zipursky,
S.L., Koonin, E.V. and Deshaies, R.J. (2002) Role of predicted
metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from
Copyright © 2012 SciRes. E NG
Cu l 1. Science 298, 6 0 8-611.
[5] Rogalla, S., Geier, C.F., Braumann, C., Ordemann, J., Müller,
J.M. and Dubiel, W. (2010) in: 45th Congress of the European
Society for Surgical Research - ESSR -, Vol. 45, pp. 17-23
(Cikirikcioglu, M., Ed.) MEDIMOND, Geneva, Switzerland.
[6] Braumann, C., Tangermann, J., Jacobi, C.A., Muller, J.M. and
Dubiel, W. (2008) Novel anti-angiogenic compounds for appli-
cation in tumor therapy - COP9 signalosome-associated kinases
as possible targ ets. Mini Rev Med C hem 8, 421 -428.
[7] Aggarwal, B.B. (2010) Targeting inflammation-induced obesity
and metabolic diseases by curcumin and other nutraceuticals.
Annu. Rev . Nu t r . 30, 1 73-199.