MINIREVIEW
New roles of flavoproteins in molecular cell biology: An
unexpected role for quinone reductases as regulators of
proteasomal degradation
Sonja Sollner and Peter Macheroux
Technische Universita
¨
t Graz, Institut fu
¨
r Biochemie, Austria
Introduction
Quinones are abundant cyclic organic compounds
present in the environment as well as in pro- and
eukaryotic cells. They can be reduced by two- or one-
electron reduction to either the hydroquinone or the
semiquinone form. A number of organisms express
enzymes that afford strict two-electron reduction to
the hydroquinone form in an attempt to avoid the
generation of semiquinones. This species is known to
cause oxidative stress by reacting with molecular oxy-
gen, eventually leading to the generation of superoxide
radicals (redox cycling). Hence, quinone reductases
(QRs) from pro- and eukaryotes have a protective
effect against quinone-related oxidative cell damage.
Consequently, QRs have been identified in bacteria,
fungi, plants and mammals.
Originally, QRs were classified as ‘DT-diaphorases’ to
express the fact that they utilize both DNPH (reduced
diphosphopyridine nucleotide, NADH) and TPNH
(reduced triphosphopyridine nucleotide, NADPH)
as a source of reducing equivalents [1]. At the time, the

tured protein has emerged. To fulfil this role, quinone reductase binds to
the core particle of the proteasome and recruits certain transcription fac-
tors such as p53 and p73a to the complex. The latter process appears to be
governed by the redox state of the flavin cofactor of the quinone reductase,
thus linking the stability of transcription factors to cellular events such as
oxidative stress. Here, we review the current evidence for protein complex
formation between quinone reductase and the 20S proteasome in
eukaryotic cells and describe the regulatory role of this complex in stabili-
zing transcription factors by acting as inhibitors of their proteasomal
degradation.
Abbreviations
NQO, mammalian NAD(P)H:quinone oxidoreductase; ODC, ornithine decarboxylase; QR, quinone reductase; ROS, reactive oxygen species.
FEBS Journal 276 (2009) 4313–4324 ª 2009 The Authors Journal compilation ª 2009 FEBS 4313
rase’, reported by Ernster & Navazio [3], is now
known as mammalian NAD(P)H:quinone oxidoreduc-
tase (NQO1, isozyme 1). However, the acronym NQO
has traditionally been confined to QRs from mamma-
lian sources.
Although the first successful crystallization of QR
was reported in the late 1980s [4,5], it was another
couple of years before Li and coworkers eventually
solved the structure of rat liver NAD(P)H:quinone oxi-
doreductase [6]. The crystal structure revealed that the
fold of the N-terminal portion resembles that of flavo-
doxin, a bacterial electron-transfer protein involved in
a variety of photosynthetic and nonphotosynthetic
reactions [7]. The biological unit for NQO1, as for
most QRs studied to date, is a dimer. The overall fold
of the flavodoxin-like catalytic domain consists of a
twisted, central five-stranded parallel b sheet sur-

others have developed a strong preference for either
NADH (e.g. AzoA from Enterococcus faecalis [11])
or NADPH (e.g. YhdA from Bacillus subtilis [12]).
By contrast, NQO2 is unable to employ NADH or
NADPH as a source of electrons, but instead uses
reduced N-ribosyl- and N-alkyl-dihydronicotinamide.
However, the issue of oxidizing substrates seems to be
far more complicated. It is generally assumed that
enzymes involved in the detoxification mechanisms of
xenobiotics do not possess endobiotic substrates but
have evolved in such a way that a broad range of
chemical structures can be processed. In fact, the size
and shape of the catalytic sites of NQO1, NQO2 and
Lot6p suggest that these enzymes have evolved to
accept a variety of ring-containing substrates. Never-
theless, a number of naturally occurring quinones com-
prising vitamin K derivatives (menaquinone and
phylloquinone), coenzyme Q (ubiquinone) and dopa-
quinone have also been shown to be substrates for
mammalian QRs [13].
The functional importance of QRs has been a matter
of discussion since their discovery. The discovery that
a vitamin K reductase, described by Maerki & Martius
[14], and the DT-diaphorase first described by Ernster
& Navazio [3] is actually the same enzyme added to
speculation revolving around the physiological role of
QRs. The opinion that mammalian QRs are primarily
involved in xenobiotic metabolism and in preventing
the carcinogenicity and toxicity of highly reactive com-
pounds is a more recent development. An explicit

ation [17]. Similarly, recent studies have demonstrated
that eukaryotic QRs bind to the 20S proteasome and
affect the lifetime of several transcription factors and
ornithine decarboxylase by inhibiting their ubitquitin-
dependent and -independent proteasomal degradation.
This role of QRs is the focus of this minireview. Before
we shed further light on this recently discovered func-
tion of a historically old enzyme family, we provide a
brief introduction to the role of the proteasome. A
more detailed description of the structure and function
of the proteasome is given in several recent review arti-
cles [18–20].
The bulk of cellular proteins in eukaryotic cells are
degraded by the 26S proteasome. This 2.5 MDa proteo-
lytic machinery consists of a 20S barrel-structured core
that provides a catalytic chamber and a 19S regulatory
particle. This latter protein complex binds to the edges
of the core particle and regulates access to the catalytic
chamber. The process that leads to proteasomal degra-
dation is initiated by selective polyubiquitination fol-
lowed by recognition of the condemned protein
through the 19S regulatory caps. Ubiquitin consists of
76 amino acids and is covalently attached in a highly
regulated multistep process to the substrate protein
[21–23]. The 19S caps are involved in recognition of
the polyubiquitinated protein substrates, unfolding of
the condemned protein [24], removing ubiquitin chains
for recycling [25,26] and opening an axial gate into the
20S catalytic chamber [27]. Whereas 26S proteasomal
degradation requires ubiquitination of substrate pro-

shown that Lot6p, a QR and ortholog of human
NQO1, is physically associated with the 20S protea-
some [34]. Using the 20S proteasome and recombi-
nant Lot6p, several biochemical issues revolving
around the stoichiometry and importance of the flavin
cofactor could be resolved. Fluorescence titration
studies exploiting the intrinsic fluorescence of the fla-
vin cofactor demonstrated that two QR dimers bind
to one 20S proteasome core particle (Fig. 1) [34].
Furthermore, QR lacking both flavin cofactors (apo-
Lot6p) was unable to bind to the proteasome, indi-
cating that the presence of the flavin cofactor is
required for complex formation. Not surprisingly, the
enzymatic activity of the QR is also compromised in
the presence of proteasome, supporting the direct or
indirect involvement of the flavin cofactor in protein
complex formation [34].
α
β
β
α
α
β
β
α
NQO1
(reduced)
Stabilization
Degradation
20S proteasome

through the gated entry port in the outer a-rings of
the core particle is considered to be the rate-limiting
step in catalysis, it appears likely that the QR binds to
or near the a-rings of the proteasome, thereby affect-
ing access to the catalytic chamber, leading to reduced
proteasomal activity [37]. In this context, it is impor-
tant to emphasize that it is not at all clear whether this
effect on proteasomal activity is part of a regulatory
mechanism because 20S proteasome core particles out-
number QR molecules by a factor of 10 [38]. Thus, it
appears that the majority of 20S core particles exist in
their ‘free’ form and only some are associated with
Lot6p. However, if the number of QR molecules
increases in the cells, for example, by overexpression
during oxidative stress, it is conceivable that 20S pro-
teasomal activity is severely downregulated by binding
of QR.
Contradictory results concerning the physical associ-
ation of the mammalian NQO1 and 20S proteasome
were recently reported by Jaiswal’s group: although
copurification of the 20S proteasome and QR from
mouse liver cytosol was observed, they were unable to
detect complex formation by immunoprecipitation
using a 20S proteasome antibody. Therefore, these
authors conclude that mammalian QR and the 20S
proteasome do not form a protein complex, as pro-
posed by others [39]. Unfortunately, no explanation
for the copurification of QR and the 20S proteasome
is provided in this report and the failure to detect the
protein complex by immunoprecipitation was not

other proteins appears to be the main pathway for
regulating proteolysis by the 26S proteasome. The
discovery by Shaul and coworkers that p53 (and other
proteins as well) is degraded more rapidly when
human QR (NQO1) is inhibited by dicoumarol, a
potent and specific inhibitor of QRs, was the first hint
that another and different regulatory pathway may
exist in eukaryotic cells. As a result of enhanced degra-
dation of p53 and hence lower levels of the trans-
cription factor, p53-dependent apoptosis in both
c-irradiated normal thymocytes and in myeloid leukae-
mic cells was suppressed. These effects could be pre-
vented by overexpression of NQO1, supporting the
idea that it might be involved in regulating cellular p53
levels [44]. These findings raised questions concerning
the role of NQO1 in ubiquitin-dependent proteasomal
degradation. Does NQO1 affect the ubiquitination
process directly or is it involved in an alternative path-
way? Further studies addressing this question revealed
that regulation of p53 degradation by NQO1 does not
require ubiquitination by Mdm2. Instead, a variant of
p53, which is resistant to Mdm2-mediated degradation,
was shown to be susceptible to dicoumarol-induced
degradation, indicating that NQO1-regulated proteaso-
mal p53 degradation is Mdm2 independent. Accord-
ingly, two alternative pathways for p53 proteasomal
degradation have been proposed: one is ubiquitin
dependent and regulated by Mdm2, whereas the other
is ubiquitin independent and regulated by the QR
NQO1, implying that p53 stabilization is not solely

ing either at the C- or the N-terminus. Currently, six
different C-terminal splicing variants have been found
in normal cells. The a-splice variant of p73 (p73a) con-
tains an additional structural domain near its C-termi-
nus known as the sterile a-motif that is probably
responsible for regulating the p53-like functions of
p73 [51]. This motif appears to be essential for inter-
action with NQO1 and subsequent stabilization as the
p73b isoform lacking the C-terminal sterile a-motif
domain was not protected against 20S proteasomal
degradation.
Recently, levels of the tumour suppressor p33
ING1b
have also been found to be regulated by NQO1. The
ING1 gene was originally identified through subtractive
hybridization between normal human mammary
epithelial cells and seven breast cancer cell lines, and
subsequent in vivo selection of genetic suppressor ele-
ments that displayed oncogenic characteristics [52].
Three alternatively spliced transcripts of the ING1 gene
have been found, encoding protein variants with a pre-
dicted size of 47, 33 and 24 kDa. p33
ING1b
(
ING1b
for
inhibitor of growth family, member 1b) has been
reported to be downregulated in several carcinomas.
The protein was shown to be a major player in cellular
stress responses, including cell-cycle arrest, apoptosis,

nucleotide). The enzyme was extensively characterized,
but was completely forgotten for several decades. In
the early 1990s, Jaiswal and coworkers isolated and
described a second NAD(P)H:quinone oxidoreductase,
which they discovered in the course of cloning human
NQO1, and named it NQO2 [39]. In 1997, Zhao et al.
demonstrated that NQO2 was indeed the flavoprotein
discovered more than 30 years before [56]. Jaiswal’s
group then developed NQO2-null mice models to
investigate the role of the second human QR in regula-
tion of p53 and found that loss of NQO2 significantly
decreases the level of p53 [39]. Co-immunoprecipita-
tion studies revealed a physical interaction of NQO2
with p53, indicating that an increased amount of
cytosolic NQO2 protects p53 from 20S proteasomal
degradation through physical association [39].
Not just transcription factors
Although transcription factors appear to be prime tar-
gets for QR-regulated degradation, recent studies have
also identified an enzyme – ornithine decarboxylase
(ODC). Catalysing the first and rate-limiting step in
the polyamine biosynthesis pathway, ODC is one of
the most labile cellular proteins [57]. The polyamines
spermidine, spermine and their precursor putrescine
are abundant polycations that are present in all living
cells. Polyamines are essential for cellular proliferation
and are involved in regulating additional fundamental
cellular processes such as cellular transformation and
differentiation [35]. In its active form, ODC is a homo-
dimer with two enzymatic active sites catalyzing the

20S proteasomal degradation, but not to degradation
by the 26S proteasome. Interaction with NQO1 pro-
tects monomeric ODC from this degradation pathway,
whereas inhibition of NQO1 dissociates the complex
and promotes ODC degradation [35,61].
Although specific mechanisms mediate the recogni-
tion of proteins destined for degradation by the 26S
proteasome, it is not yet clear how proteins are recog-
nized for degradation by the 20S core particle. Recent
studies have suggested that unstructured proteins such
as a-synuclein and p21
cip
are intrinsically unstable
because of their capacity to enter the 20S proteasome
pore [62,63]. Even a segment of unstructured region
within a protein might be sufficient to direct a protein
to 20S proteasomal degradation. Analysis of the ODC
sequence using different computational prediction
algorithms indicates that ODC contains several
unstructured regions. Similarly, > 80% of transcrip-
tion factors have been reported to possess extended
regions of intrinsic disorder [64].
From mammalian cells to yeast:
a homologous system in a unicellular
organism
All of the initial studies indicating a role for QR in
stabilizing transcription factors and tumour suppressors
were performed with cells from a narrow range of
multicellular eukaryotic organisms, i.e. mammalian
cells of human or murine origin. Until recently, it was

that the native dimeric quaternary structure is a prere-
quisite for formation of the ternary complex: in its
monomeric form, Lot6p still binds to the proteasome,
but is no longer able to recruit the transcription factor
to the complex. Degradation of Yap4p by the 20S pro-
teasome is prevented by the formation of a ternary
protein complex consisting of the 20S core particle,
reduced Lot6p and Yap4p. Interestingly, formation of
this ternary protein complex not only prevents degra-
dation of Yap4p, but also influences the localization of
the transcription factor. In normal, unstressed yeast
cells, Yap4p is present in the cytosol, whereas under
oxidative stress it relocates to the nucleus. Apparently,
oxidation of the flavin cofactor of Lot6p results in the
dissociation and concomitant relocalization of the
released transcription factor to the nucleus where
expression of stress related genes then occurs.
Taken together, several studies investigating tran-
scription factors from mammalian to yeast cells, as
well as regulatory proteins such as ODC, suggest that
short-lived proteins are intrinsically prone to degrada-
tion by the 20S proteasome. The association of a QR
(NQO1, NQO2 or Lot6p) with the 20S proteasome,
together with its ability to regulate the stability, and in
Quinone reductase as regulator of the proteasome S. Sollner and P. Macheroux
4318 FEBS Journal 276 (2009) 4313–4324 ª 2009 The Authors Journal compilation ª 2009 FEBS
the case of the yeast system, even the localization, of
those short-lived proteins suggests that QRs might play
a general and central role in regulating the metabolic
stability of a subset of cellular proteins.

reduction of the isoalloxazine ring system may cause
reorganization of hydrogen-bond interactions with
neighbouring amino acids, which in turn may lead to
local structural changes in the protein. An instructive
example for such a restructuring is given by the X-ray
analysis of oxidized and reduced flavodoxin from Clos-
tridium beijerinckii [68]. In the oxidized state, C@Oof
Gly57 points away from N(5) of the isoalloxazine ring
system. Upon reduction, the C@O turns towards the
N(5) position to form a hydrogen bond. As a result,
Gly57 adopts a different conformation and this ‘pep-
tide flip’ also causes the movement of some amino acid
side chains (Fig. 2) [68]. As mentioned in the introduc-
tion, QRs also adopt a flavodoxin-fold and the isoal-
loxazine ring engages in a similar interaction with a
peptide chain. In the reported structure of oxidized
Lot6p, the backbone amide group of Asn96 forms a
hydrogen bond to N(5). Upon reduction, N(5) will be
protonated and hence this interaction is no longer
feasible, and it is conceivable that this leads to a con-
formational change similar to that observed in flavo-
doxins. Interestingly, structural comparison of QRs
(human NQO1, human NQO2, mouse NQO1 and
yeast Lot6p; Fig. 3) shows the conservation of large
hydrophobic amino acid residues (i.e. conservation of
a Trp residue; Fig. 3E) in the peptide segment that
runs along the N(5)–C(4)=O edge of the isoalloxazine
ring system. It is conceivable that a similar peptide flip
occurs in QRs upon reduction, which then results in a
repositioning of these large hydrophobic side chains

[70]. Thus, it is conceivable that a similar mechanism
is used by QRs for sensing and binding of intrinsically
unfolded proteins such as transcription factors. This
mechanism could be probed by combined structure–
function analysis of oxidized and reduced QR and
mutagenesis of conserved residues.
As far as the transcription factor p53 is concerned,
several amino acid residues have been implicated in
the interaction with NQO1. This tumour suppressor
is mutated in > 50% of human cancers [43], with
Arg175His, Arg248His and Arg273His being the most
frequent ‘hot-spot’ mutants [71]. Mutations in the p53
gene often result in the accumulation of p53 protein
variants in human cancer cells [72]. Asher and cowork-
ers investigated whether those common mutations may
have an effect on binding of p53 to NQO1. They
showed that the most frequent p53 variants in human
cancer mentioned above were resistant to dicoumarol-
induced degradation (unlike wild-type p53), probably
A
B
C
D
E
Fig. 3. Comparison of the loops close to
the flavin N(5) of several quinone reducta-
ses. (A) NQO1 from Homo sapiens (PDB
code 1d4a). (B) NQO2 from H. sapiens
(PDB code 1qr2). (C) NQO1 from Mus
musculus (PDB code 1dxq). (D) Lot6p from

tive pathways for p53 degradation, the NQO1 depen-
dent and the Mdm2 dependent, must have different
p53 structural requirements. Crystal structures of com-
plexes between the core domain of human p53 and
DNA half-sites reveal that two of the three residues
mentioned above (Arg248, Arg273) are located at the
interface of p53 and the DNA helix [76,77], indicating
that the same residues that are involved in DNA
recognition and binding are actually responsible for
association of p53 with NQO1 (Fig. 4).
Conclusions and open questions
The last decade has witnessed accumulating evidence
for a role of eukaryotic QRs in regulating the 20S pro-
teasomal degradation of certain transcription factors
(e.g. p53, Yap4p) and possibly proteins possessing a
high degree of unstructured segments (e.g. ODC). The
body of information available clearly indicates that
this pathway is relevant for the cell and complements
other pathways such as ubiquitin-dependent 26S prote-
asomal degradation mediated by Mdm2. The concept
of protecting a protein by ‘hiding it near the lion’s
den’ (the catalytic chamber of the proteasome) is at
first unexpected. However, the proteasome represents
an enormous surface (213 210 A
˚
2
) [78] that offers itself
for extensive protein–protein interactions and perhaps
the interaction of QR and the 20S proteasome is just
one example of many others still to be discovered.

Hum Genomics 2, 329–335.
3 Ernster L & Navazio F (1958) Soluble diaphorase in
animal tissue. Acta Chem Scand 12, 595–602.
4 Amzel LM, Bryant SH, Prochaska HJ & Talalay P
(1986) Preliminary crystallographic X-ray data for an
NAD(P)H:quinone reductase from mouse liver. J Biol
Chem 261, 1379.
5 Ysern X & Prochaska HJ (1989) X-ray diffraction anal-
yses of crystals of rat liver NAD(P)H:(quinone-accep-
tor) oxidoreductase containing cibacron blue. J Biol
Chem 264, 7765–7767.
6 Li R, Bianchet MA, Talalay P & Amzel LM (1995) The
three-dimensional structure of NAD(P)H:quinone
reductase, a flavoprotein involved in cancer chemopro-
tection and chemotherapy: mechanism of the two-elec-
tron reduction. Proc Natl Acad Sci USA 92, 8846–8850.
7 Sancho J (2006) Flavodoxins: sequence, folding, binding,
function and beyond. Cell Mol Life Sci 63, 855–864.
8 Foster CE, Bianchet MA, Talalay P, Zhao Q & Amzel
LM (1999) Crystal structure of human quinone reduc-
tase type 2, a metalloflavoprotein. Biochemistry 38,
9881–9886.
9 Liger D, Graille M, Zhou CZ, Leulliot N, Quevillon-
Cheruel S, Blondeau K, Janin J & van TH (2004) Crystal
structure and functional characterization of yeast
YLR011wp, an enzyme with NAD(P)H-FMN and ferric
iron reductase activities. J Biol Chem 279, 34890–34897.
10 Iyanagi T & Yamazaki I (1970) One-electron-transfer
reactions in biochemical systems V. Difference in
the mechanism of quinone reduction by the NADH

Huber R (2005) Molecular machines for protein degra-
dation. Chembiochem 6, 222–256.
19 Groll M & Clausen T (2003) Molecular shredders: how
proteasomes fulfill their role. Curr Opin Struct Biol 13,
665–673.
20 Groll M & Huber R (2003) Substrate access and pro-
cessing by the 20S proteasome core particle. Int J Bio-
chem Cell Biol 35, 606–616.
21 Hershko A & Ciechanover A (1998) The ubiquitin sys-
tem. Annu Rev Biochem 67, 425–479.
22 Glickman MH & Ciechanover A (2002) The ubiquitin–
proteasome proteolytic pathway: destruction for the
sake of construction. Physiol Rev 82, 373–428.
23 Asher G & Shaul Y (2006) Ubiquitin-independent deg-
radation: lessons from the p53 model. Isr Med Assoc J
8, 229–232.
24 Pickart CM & Cohen RE (2004) Proteasomes and their
kin: proteases in the machine age. Nat Rev Mol Cell
Biol 5, 177–187.
25 Verma R, Aravind L, Oania R, McDonald WH,
Yates JR III, Koonin EV & Deshaies RJ (2002) Role
of Rpn11 metalloprotease in deubiquitination and
degradation by the 26S proteasome. Science 298, 611–
615.
26 Yao T & Cohen RE (2002) A cryptic protease couples
deubiquitination and degradation by the proteasome.
Nature 419, 403–407.
27 Kohler A, Cascio P, Leggett DS, Woo KM, Goldberg
AL & Finley D (2001) The axial channel of the protea-
some core particle is gated by the Rpt2 ATPase and

J Biol Chem 279, 52390–52398.
34 Sollner S, Schober M, Wagner A, Prem A, Lorkova L,
Palfey BA, Groll M & Macheroux P (2009) Quinone
reductase acts as a redox switch of the 20S yeast pro-
teasome. EMBO Rep 10, 65–70.
35 Kahana C, Asher G & Shaul Y (2005) Mechanisms of
protein degradation: an odyssey with ODC. Cell Cycle
4, 1461–1464.
36 Orlowski M, Cardozo C & Michaud C (1993) Evidence
for the presence of five distinct proteolytic components
in the pituitary multicatalytic proteinase complex.
Properties of two components cleaving bonds on the
carboxyl side of branched chain and small neutral
amino acids. Biochemistry 32, 1563–1572.
37 Groll M, Ditzel L, Lowe J, Stock D, Bochtler M,
Bartunik HD & Huber R (1997) Structure of 20S
proteasome from yeast at 2.4 A
˚
resolution. Nature 386,
463–471.
38 Ghaemmaghami S, Huh WK, Bower K, Howson RW,
Belle A, Dephoure N, O’Shea EK & Weissman JS
(2003) Global analysis of protein expression in yeast.
Nature 425, 737–741.
39 Gong X, Kole L, Iskander K & Jaiswal AK (2007)
NRH:quinone oxidoreductase 2 and NAD(P)H:quinone
oxidoreductase 1 protect tumor suppressor p53 against
Quinone reductase as regulator of the proteasome S. Sollner and P. Macheroux
4322 FEBS Journal 276 (2009) 4313–4324 ª 2009 The Authors Journal compilation ª 2009 FEBS
20S proteasomal degradation leading to stabilization

oxidoreductase 1 in HeLa cells: role of hydrogen per-
oxide and growth phase. J Biol Chem 276, 44379–
44384.
49 Kaghad M, Bonnet H, Yang A, Creancier L, Biscan
JC, Valent A, Minty A, Chalon P, Lelias JM Dumont
X et al. (1997) Monoallelically expressed gene related to
p53 at 1p36, a region frequently deleted in neuroblas-
toma and other human cancers. Cell 90, 809–819.
50 Davis PK & Dowdy SF (2001) p73. Int J Biochem Cell
Biol 33, 935–939.
51 Wang WK, Bycroft M, Foster NW, Buckle AM, Fersht
AR & Chen YW (2001) Structure of the C-terminal
sterile alpha-motif (SAM) domain of human p73 alpha.
Acta Crystallogr D Biol Crystallogr 57, 545–551.
52 Garkavtsev I, Kazarov A, Gudkov A & Riabowol K
(1996) Suppression of the novel growth inhibitor
p33ING1 promotes neoplastic transformation. Nat
Genet 14, 415–420.
53 Campos EI, Chin MY, Kuo WH & Li G (2004) Biolog-
ical functions of the ING family tumor suppressors.
Cell Mol Life Sci 61, 2597–2613.
54 Garate M, Campos EI, Bush JA, Xiao H & Li G
(2007) Phosphorylation of the tumor suppressor
p33(ING1b) at Ser-126 influences its protein stability
and proliferation of melanoma cells. FASEB J 21,
3705–3716.
55 Garate M, Wong RP, Campos EI, Wang Y & Li G
(2008) NAD(P)H quinone oxidoreductase 1 inhibits the
proteasomal degradation of the tumour suppressor
p33(ING1b). EMBO Rep 9, 576–581.

Science 299, 408–411.
64 Liu J, Perumal NB, Oldfield CJ, Su EW, Uversky VN
& Dunker AK (2006) Intrinsic disorder in transcription
factors. Biochemistry 45, 6873–6888.
65 Mendizabal I, Rios G, Mulet JM, Serrano R,
de Larrinoa IF (1998) Yeast putative transcription
factors involved in salt tolerance. FEBS Lett 425,
323–328.
66 Furuchi T, Ishikawa H, Miura N, Ishizuka M, Kajiya
K, Kuge S & Naganuma A (2001) Two nuclear
proteins, Cin5 and Ydr259c, confer resistance to
cisplatin in Saccharomyces cerevisiae. Mol Pharmacol
59, 470–474.
67 Asher G, Lotem J, Kama R, Sachs L & Shaul Y (2002)
NQO1 stabilizes p53 through a distinct pathway. Proc
Natl Acad Sci USA 99, 3099–3104.
68 Ludwig ML, Pattridge KA, Metzger AL, Dixon MM,
Eren M, Feng Y & Swenson RP (1997) Control of
oxidation–reduction potentials in flavodoxin from
S. Sollner and P. Macheroux Quinone reductase as regulator of the proteasome
FEBS Journal 276 (2009) 4313–4324 ª 2009 The Authors Journal compilation ª 2009 FEBS 4323
Clostridium beijerinckii: the role of conformation
changes. Biochemistry 36, 1259–1280.
69 Harrison SC (1996) Peptide–surface association: the
case of PDZ and PTB domains. Cell 86, 341–343.
70 Reddy GB, Kumar PA & Kumar MS (2006) Chaper-
one-like activity and hydrophobicity of alpha-crystallin.
IUBMB Life 58, 632–641.
71 Prives C (1994) How loops, beta sheets, and
alpha helices help us to understand p53. Cell 78, 543–