Karen Bedard and Karl-Heinz Krause

phagosomal or the plasma membrane (97, 286, 304). This
fusion is thought to be a key event for the microbicidal
activity of NOX2. However, NOX2 can also be activated
within the granules without a need for fusion with surface
membranes (562, 898). The resulting intracellular ROS
generation might be involved in signaling functions of
NOX2 (439).
In cells other than phagocytes, the subcellular distribution
varies depending on the specific cell type. In
smooth muscle cells, NOX2 is found to colocalize with the
perinuclear cytoskeleton (538). In hippocampal neurons,
NOX2 is suggested to be localized in the membranes of
synaptic sites (866), possibly playing a role in superoxidedependent
long-term potentiation and memory function.
The human and mouse NOX2 gene is located on the
X chromosome. At the transcriptional level, a promoter
region sufficient for NOX2 expression in monocytes lies in
the 450-bp region before the transcriptional start site
(818). However, additional regulatory regions located up
to 60 kb upstream from the start site also influence expression,
with sensitive regions at �13, �15, �28, and
�29 kb (545). NOX2 gene expression is regulated by
repressing and activating factors. Repressing factors include
the CCAAT displacement protein (CDP) (563, 819),
HOXA10, and Meis1 (76). Activating factors include PU.1,
Elf-1, YY1, and interferon regulatory factors IRF1 and
IRF2 (243, 422, 850, 924), NF�B (28), HOXA9 (76), and
PB1 (76). The PU.1 transcription factor appears to have a
particularly important role in the expression of NOX2, as
PU.1-deficient mice fail to express NOX2 (850). Mutations
in the NOX2 promoter region at positions �53, �52, or
�50 interfere with PU.1 binding, and CGD patients with
such mutations do not express NOX2 in neutrophils,
monocytes, and B lymphocytes. However, the importance
of the PU.1 promoter may be somewhat cell specific, as
these patients do express NOX2 in eosinophils (850).
NOX2 gene expression is inducible. This has been
demonstrated in phagocytes in response to interferon-�
(mRNA) (654), in myofibroblasts after carotid artery injury
(mRNA) (856), and in cardiomyocytes after acute
myocardial infarction (protein) (488). NOX2 expression is
also increased in response to angiotensin II in adipose
tissue (mRNA) (359), aorta (mRNA) (359), heart (mRNA)
(359), resistance artery vascular smooth muscle cells
(mRNA and protein) (881), and pancreatic islets (protein)
(648). Note however that an increase in NOX2 levels is not
invariably due to transciptional activation. In the case of
resistance arteries, the angiotensin II-induced NOX2 elevation
may be due to increased de novo protein synthesis,
regulated at a posttranscriptional level (881).
2. NOX1
NOX1 was the first homolog of NOX2 (then called
gp91 phox ) to be described (55, 841). NOX1 and NOX2
THE NOX FAMILY OF ROS-GENERATING NADPH OXIDASES 251
Physiol Rev VOL 87 JANUARY 2007 www.prv.org
genes appear to be the result of a relatively recent gene
duplication, as the number and the length of the exons is
virtually identical between the two genes (53). Similarly,
at the protein level, there is a high degree of sequence
identity (�60%) between NOX1 and NOX2 (55, 841). The
human and mouse NOX1 gene is located on the X chromosome.
An alternatively spliced form of NOX1 lacks
exon 11 (55, 296, 353). It appears that this splice variant
encodes a protein incapable of producing superoxide
(296). The existence of a second very short isoform of
NOX1 had been suggested; however, this turned out to be
an artifact due to the formation of a stable loop in the
NOX1 mRNA (see Refs. 55, 296, 353). In mouse, several
other splice variants due to the use of alternative promoters
have been described (29). Most studies suggest a
molecular mass of NOX1 in the range of 55–60 kDa (24,
178, 425). If these values are correct, NOX1 is most likely
not N-glycosylated, despite the presence of two NXT/S
consensus glycosylation sites in the extracellular domains.
The message for NOX1 is most highly expressed in
colon epithelium (53, 841, 854); however, it is also expressed
in a variety of other cell types, including vascular smooth
muscle cells (510, 841), endothelial cells (14, 473), uterus
(55, 841), placenta (178), prostate (55, 841), osteoclasts
(516), retinal pericytes (576), as well as in several cell lines,
such as the colon tumor cell lines Caco-2 (159, 701), DLD-1
(701), and HT-29 (701) and the pulmonary epithelial cell line
A549 (320). Expression of NOX1 in the gastric mucosa is
species dependent. It was not found in human stomach
(770) but is functionally expressed in guinea pig stomach pit
cells and mucosal cells (444, 447, 868).
In addition to its constitutive expression in a variety
of tissues, the NOX1 message is induced under many
circumstances. In vascular smooth muscle, platelet-derived
growth factor (PDGF), prostaglandin F 2�, and angiotensin
II induce NOX1 expression (441, 510, 841, 955).
NOX1 is upregulated in restenosing carotid artery after
injury (856) and in prostate in response to castration
(859). Other conditions where NOX1 upregulation is observed
include interferon-� addition to Caco-2 colonocytes
(295), Ras expression in rat kidney cells (614),
BMP4 stimulation of endothelial cells (823), and Helicobacter
pylori lipopolysaccharide stimulation of guinea pig
gastric mucosal cells (443). Studies on the inducible expression
of NOX1 in the vascular system suggest an involvement
of epidermal growth factor (EGF) receptor
transactivation and involvement of ATF-1, phosphatidylinositol
3-kinase, and protein kinase C (PKC)-� (252). In
renal mesangial cells, nitric oxide downregulates NOX1
(mRNA and protein) (707).
The 5’-region of the human NOX1 gene contains binding
elements for signal transducers and activators of transcription
(STATs), interferon regulatory factor (IRF),
AP-1, NF�B, CREB, CBP/p300 elements (498), and GATA
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