Cellular Signalling 23 (2011) 747–752

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Cellular Signalling
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c e l l s i g

Review

Control of p53 and NF-κB signaling by WIP1 and MIF: Role in cellular senescence and
organismal aging
Antero Salminen a,b,⁎, Kai Kaarniranta c,d
a
Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland
b
Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland
c
Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland
d
Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland

a r t i c l e i n f o a b s t r a c t

Article history: The stress-activated signaling pathways, p53 and NF-κB, have a major role in the regulation of cellular
Received 7 September 2010 senescence and organismal aging. These ancient signaling networks display functional antagonism via
Accepted 1 October 2010 negative autoregulatory circuits. WIP1 (wildtype p53-induced phosphatase 1) and MIF (macrophage
Available online 16 October 2010
migration inhibitory factor) are signaling molecules which link together the p53 and NF-κB pathways via
positive and negative feedback loops. It seems that the efficiency of the p53 signaling pathway declines
Keywords:
Cellular senescence
during aging whereas that of NF-κB is clearly enhanced. Moreover, p53 is an important trigger of cellular
Inflammaging senescence while NF-κB signaling seems to be involved in the induction of the senescence-associated
NF-κB secretory phenotype (SASP). MIF is a pro-inflammatory cytokine which inhibits the function of p53 signaling
p53 whereas it is linked to NF-κB signaling via a positive feedback loop. MIF knockout mice are healthier and live
WIP1 longer than their wild-type counterparts. An increased level of MIF can support inflammatory responses via
MIF enhancing NF-κB signaling and repressing the function of p53. p53 is an inducer of the expression of WIP1
which can subsequently inhibit NF-κB signaling. Several observations indicate that the activity of WIP1
decreases during the aging process, this being probably attributable to the decline in p53 function. Decreased
WIP1 activity potentiates the activity of p38MAPK and NF-κB signaling leading to premature cellular
senescence as well as low-level chronic inflammation. We will review the findings linking WIP1 and MIF to
specific signaling responses of p53 and NF-κB and discuss their role in the regulation of cellular senescence
and organismal aging.
© 2010 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
2. WIP1 and MIF: a background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
2.1. WIP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
2.2. MIF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
3. Interactions of WIP1 and MIF with p53 and NF-κB signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
4. WIP1 and MIF: regulation of cellular senescence and organismal aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751

1. Introduction

Senescence is a cellular state involving an irreversible arrest of cell

⁎ Corresponding author. Department of Neurology, Institute of Clinical Medicine,
School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio,
Finland. Tel.: +358 505740740; fax: +358 17162048.
E-mail address: antero.salminen@uef.fi (A. Salminen).
proliferation. It can be induced by a variety of stress insults including
DNA damage, telomere shortening, and epigenetic changes [1–3].
Cellular senescence is an important biological host defence mechanism
preventing neoplastic changes which could lead to tumorigenesis
and loss of tissue integrity. For instance, oncogene-induced cellular

0898-6568/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.cellsig.2010.10.012
748 A. Salminen, K. Kaarniranta / Cellular Signalling 23 (2011) 747–752
senescence is one way to restrict the growth of benign tumors [4].
Senescent cells display a flat morphology in cell culture and undergo
several molecular changes, e.g. (i) activation of p53/pRB signaling via
the p16INK4a/ARF proteins, (ii) appearance of senescence-associated
heterochromatin foci (SAHF) and (iii) activation of lysosomal β-
galactosidase activity (SA-β-Gal) [2,3,5]. Recent studies have demon-
strated that senescent cells secrete many pro-inflammatory factors
and thus the condition has been called senescence-associated
secretory phenotype (SASP) [6,7]. The secretion contains many
compounds e.g. interleukins, chemokines, growth factors, and matrix
metalloproteinases. Pro-inflammatory factors can potentiate the
arrest of the cell cycle, remodel the extracellular matrix, and recruit
macrophages to help cleanse possible apoptotic and necrotic cell
injuries. It has been postulated that persistent SASP, such as occurs
during aging, can promote tumor progression and also support
organismal aging [7–9]. Interestingly, low-level chronic inflammation
has been linked to the aging process in vivo [10–12]. Whether this is
triggered by the accumulation of senescent cells into tissues or via
some other mechanism still needs to be clarified.
There has been intense research activity focused on the signaling
mechanisms linked to cellular senescence since these mechanisms are
believed to be also associated with the control of cancer and
organismal aging. There is growing evidence indicating that the p53
suppressor oncogene has a key role in the regulation of the cell fate in
apoptosis, cancer, cellular senescence and organismal aging [1–3]. It
seems that several stress-activated pathways convene to trigger the
activation of p53. The activity of p53 is controlled mostly at the post-
translational level, i.e. p53 protein can be modified by acetylation,
phosphorylation, methylation, ubiquitination, sumoylation, neddyla-
tion, and glycosylation [13,14]. Crucial upstream regulators of p53 are
p16INK4a/ARF proteins, common activators in cellular stress, and
MDM2, a well-known inhibitor of p53. Upregulation of p16INK4a is a
biochemical hallmark of both cellular senescence and the aging
process [1,15]. Stress signaling pathways induced by the polycomb
group (PcG) and p38MAPK kinase converge in the regulation of
p16INK4a/ARF activity. The p53 signaling can either regulate directly
or via pRB binding a number of cellular functions, e.g. proliferation
arrest, cellular metabolism, and epigenetic heterochromatin forma-
tion, which are all associated with aging/senescence processes.
The function of the p53 signaling network is known to involve
direct interactions with approx. 100 proteins, and indirect synergistic
and antagonistic functions with many central signaling pathways. The
p53 signaling shows a functional antagonism with NF-κB system, an
important stress pathway e.g. regulating immune responses, apopto-
sis, and cellular proliferation [14,16]. There is emerging evidence
indicating that NF-κB and C/EBP are the critical signaling systems
stimulating and maintaining SASP in cellular senescence [7]. Many
approaches have also demonstrated that the NF-κB system is the
culprit in the activation of chronic inflammation in the aging process
itself and in several age-related diseases [11,17,18]. There are some
observations that p53 can inhibit inflammatory responses, probably
via opposing the NF-κB signaling [see later discussion, 14,19].
This raises the question how can two antagonistic signaling
systems control the appearance of cellular senescence and all of
the associated conditions? It appears that the intervening signaling
proteins between p53 and NF-κB pathways have a fundamental role
in the outcome of p53 and NF-κB signaling. We will review here the
functions of WIP1 (wildtype p53-induced phosphatase 1) and MIF
(macrophage migration inhibitory factor) in the regulation of p53 and
NF-κB signaling, via positive and negative feedback loops, in the
occurrence of cellular senescence and organismal aging.
2. WIP1 and MIF: a background
The p53 and NF-κB signaling networks have their origins early
in evolution and they have major functions in host defence. p53 is
the so-called guardian of the genome and a key regulator of cell death.
NF-κB signaling is crucial in the immune defence of the organism but
it has several functions related to cell cycle regulation and apoptosis.
There is emerging data that p53 and NF-κB signaling are linked to
each other via metabolic regulation as well as in the regulation of
cellular senescence and aging process. It is important to recognize the
connecting mechanisms between these two pathways if one wishes to
understand the coordinated functions of these signaling networks.
WIP1 and MIF are important proteins which can link p53 and NF-κB
signaling cascades to each other (Fig. 1) and moreover, they both can
coordinate their involvement e.g. in tumorigenesis and inflammation
[20–22].
2.1. WIP1
WIP1 is a type 2C protein phosphatase (PP2Cδ) which inhibits the
function of several p53-dependent tumor suppressor pathways, e.g.
ATM-CHK2–p53 and p38MAPK–p53 pathways [20,23]. In 1997,
Fiscella et al. [24] cloned the novel PPM1D gene, coding the WIP1
protein, which was activated by DNA damage in a p53-dependent
manner. The WIP1 protein is a Mg2+-dependent but okadaic acid
insensitive phosphatase. The target proteins of WIP1 include p53,
p38MAPK, ATM, CHK2, MDM2, and the p65 component of NF-κB
complex [23,25]. WIP1 is a novel oncogene which is overexpressed in
many cancers [20]. In contrast, WIP1-deficient cells display an
upregulation of INK4a and ARF, important regulators in cellular
senescence. WIP1 null mice are viable but show postnatal defects
e.g. in organogenesis, immune function and cell cycle control [26].
Interestingly, these mice are resistant to common cancer genes [27].
This seems to be attributable to the induction of p16INK4a/ARF–p53
pathway via the activation of p38MAPK and ATM-CHK2 signaling
in the null mice [28,29]. Recent studies have indicated that WIP1 can
coordinate DNA damage response by antagonizing the activation of
ATM-CHK2-p53 pathway. This is triggered by an oscillatory negative
feedback loop within the p53 response [20,30]. This feedback
regulation can also be modified by miR-16 which inhibits WIP
expression [31]. Currently, WIP1 is a promising drug discovery target
for cancer therapy.
2.2. MIF
MIF is an evolutionarily conserved cytokine which is expressed
not only in the immune system but also in several other cells, e.g.
endothelial, epithelial and neuronal cells. MIF is a pro-inflammatory
cytokine which has been implicated in the pathogenesis of several
inflammatory diseases, e.g. atherosclerosis and rheumatoid arthritis,
and autoimmune diseases [21,22]. The central role of MIF in immune
defence is highlighted by the observations that MIF can counteract the
anti-inflammatory effects of glucocorticoids, in particular in systemic
inflammatory disorders [32]. Currently, MIF is a promising therapeutic
target in several inflammatory diseases [33]. MIF is a pleiotrophic
Fig. 1. A schematic presentation depicting the position of WIP1 (A) and MIF (B) at the
crossroads between autoregulatory feedback loops coordinated by p53 and NF-κB
signaling pathways.
 A. Salminen, K. Kaarniranta / Cellular Signalling 23 (2011) 747–752
factor which can also promote tumor growth and angiogenesis
[21,22,34]. These effects are probably linked to the ability of MIF to
increase resistance to apoptosis by activating the NF-κB system
and repressing p53 function (Fig. 1B). Recently, it was demonstrated
that MIF regulates glucose homeostasis, i.e. it promotes insulin secre-
tion in pancreatic beta cells and modulates glucose uptake, glycolysis
and insulin resistance in the target tissues [35,36]. Verschuren
et al. [37] demonstrated that MIF deficiency in mice could reduce
chronic inflammation in white adipose tissue and liver, impair the
development of insulin resistance, and prevent the appearance
of atherosclerotic lesions. These observations indicate that MIF has
a crucial role in obesity and in the development of types 1 and 2
diabetes and associated comorbidities.
In 2003, Leng et al. [38] cloned a cell surface receptor for MIF which
was CD74, a widely expressed type II transmembrane protein. The
functional MIF receptor is made up of a heteromeric complex between
CD74 and CD44 [39]. Later studies revealed that CD74 can also
assemble a heteromeric receptor with the chemokine receptor CXCR2
and CXCR4 which may explain some of the chemokine-like functions
of MIF [40]. MIF can induce several signaling cascades via CD74/CD44
receptor, e.g. ERK1/2, PI3K/Akt, NF-κB pathways [34,41,42]. MIF
signaling is known to activate several transcription factors, e.g. Elk-1
and NF-κB which mediate inflammatory and tumorigenic signaling
[41–43]. MIF signaling also activates some stress kinases, e.g. AMP-
kinase and Src, but inhibits JNK activity which all have tissue-specific
effects in host defence [44,45]. Kleeman et al. [45] demonstrated
that MIF can bind Jab1 (Jun activation domain-binding protein 1) in
the cytoplasm and inhibit JNK activity and stimulus-enhanced AP-1
activity. It has been reported that Jab1 can regulate many important
cellular functions, e.g. participating in the nuclear export of proteins
which are subsequently broken down in proteasomes [46]. Interest-
ingly, Jab1 can bind to nuclear p53 and coordinate its export into
the cytosol where it is degraded. By binding to Jab1, MIF can modulate
the maintenance of p53 homeostasis [46]. Overall, the signaling
connections induced by MIF still need to be elucidated in order to
facilitate understanding of its pleiotrophic, most likely tissue-specific,
functions.
3. Interactions of WIP1 and MIF with p53 and NF-κB signaling
Signaling pathways can control their own functions via positive
and negative autoregulatory feedback circuits [47]. Moreover, these
loops can be integrated with each other and in that way the activation
of one loop can regulate the activity of some other pathway. This
increases the oscillation and dynamic activity between signaling
cascades [48]. The NF-κB system is an excellent example of a signaling
pathway which has several autoregulatory feedback circuits, e.g.
negative feedback loops for the termination of NF-κB response after
the resolution of inflammation [49,50]. The regulation of p53 function
also involves a complex set of positive and negative autoregulatory
loops [51]. In this respect, it is interesting that these ancient signaling
systems of host defence have adopted clearly different functional
strategies, i.e. the NF-κB system responds mainly to extrinsic stresses
whereas p53 signaling controls the cell cycle, apoptosis, metabolic
patterns, and cellular senescence [14]. In addition, on many occasions,
the p53 and NF-κB pathways display a crucial functional antagonism,
e.g. in the regulation of cell cycle and apoptotic cell death. It seems
that the signaling components which are involved in the loops of
both p53 and NF-κB systems may integrate the opposite functions of
these pathways. We will focus on the WIP1 and MIF factors which are
partners in the autoregulatory loops of both p53 and NF-κB (Fig. 1).
By definition, the expression of WIP1 is induced by p53 signaling
[see earlier discussion, 24]. The promoter sequences of WIP1 contain a
conserved p53 response element which mediates the p53-dependent
induction of WIP1 expression [52]. Stresses, such as UV radiation, can
trigger the expression of WIP1 via the p38MAPK–p53 and the JNK–c-
749
Jun pathways [53,54]. c-Jun also binds to the WIP promoter and
competes with p53 in the transactivation process. There seems to
be a negative feedback regulation between p53 and WIP1 in the
activation loop (Fig. 1A). Takekawa et al. [53] demonstrated that
WIP1 phosphatase can selectively inactivate p38MAPK and p53
by dephosphorylating specific threonine and serine residues. WIP1
overexpression suppressed the p53-mediated apoptosis after UV
radiation, indicating that this is a functional feedback inhibition. A
negative feedback loop between WIP1 and p53 has been observed
under different circumstances and it can recruit ATM/CHK2 to
coordinate the oscillation of the p53 response after DNA damage
[20,55].
Recently, Chew et al. [25] demonstrated that WIP1 phosphatase
can inhibit NF-κB signaling by dephosphorylating the Ser536 residue
of the p65 subunit. Phosphorylation of Ser536 in p65 is required for
the transactivation by NF-κB complex. In addition, these workers
demonstrated that WIP1 can also repress the transactivation capacity
of p65 subunit via the dephosphorylation of the p38MAPK, one of the
kinases activating NF-κB signaling. Overexpression of WIP1 clearly
inhibited the activation of NF-κB in response to TNF-α treatment.
Chew et al. [25] also observed that the lack of WIP1 could induce a
dramatic hyperactivation of NF-κB system in cultured cells exposed to
LPS and evoked an overt inflammatory response in WIP1 null mice.
They also demonstrated that the expression of WIP1 was clearly
reduced in the monocytes of sepsis patients. All these observations
demonstrate that WIP1 is a potent inhibitor of the NF-κB system
and combined with the activation of WIP1 by p53 explains why p53
is an inhibitor of NF-κB driven disorders in many situations, e.g. in
inflammatory responses [19] (Fig. 1A).
On the other hand, Lowe et al. [56] demonstrated that WIP1 gene,
PPM1D, was a transcriptional target of NF-κB in breast cancer cells.
The expression of WIP1, both at mRNA and protein levels, was
correlated with the activation degree of NF-κB. They observed that
the promoter of PPM1D gene contained an evolutionarily conserved
NF-κB binding site. They also established that NF-κB complex could
bind to that target sequence and functionally activate the PPM1D
promoter. It is probable that the activation of WIP1 expression by NF-
κB is able to enhance tumorigenesis and suppress cellular senescence
(see above). It is known that NF-κB can support cancer development
with some other mechanisms, e.g. via the activation of IAP (inhibitor
of apoptosis) expression [57]. Taken together, WIP1 seems to form
negative feedback loops with both p53 and NF-κB pathways (Fig. 1A).
It appears that the antagonism between p53 and NF-κB signaling could
be partly attributable to the position of WIP1 in these autoregulatory
circuits.
MIF is also involved in the autoregulatory loops with p53 and NF-
κB (Fig. 1B). In 1999, Hudson et al. [58] observed using a functional
screening technique that MIF could inhibit the p53-mediated growth
arrest and apoptosis. Later, Mitchell et al. [59] demonstrated that MIF
reduced the cellular activity of p53 which could trigger a sustained
pro-inflammatory phenotype in macrophages. Several studies have
reported that MIF can inhibit the function of p53 and subsequently
enhance cancerous growth [21,22,34]. It seems that the inhibition of
Jab1-driven p53 export from the nuclei and degradation could
represent the molecular basis for the MIF-induced p53 repression
(see above) [45,46]. Recently, Jung et al. [60] demonstrated that MIF
can physically interact with p53 protein, both in vitro and in vivo. They
observed that the Cys81 residue of MIF protein was the crucial residue
in the binding of p53 and MIF. They also revealed that MIF prevented
the translocation of p53 from the cytoplasm to the nucleus. MIF could
also stabilize the complex between p53 and MDM2 and thus inhibited
p53 activity [60].
Several studies have indicated that hypoxia, particularly HIF-1
(hypoxia-inducible factor-1) activation, is a potent inducer of MIF
which could explain the extensive expression of MIF in tumors
(Fig. 1B). Baugh et al. [61] were the first to demonstrate that the
750 A. Salminen, K. Kaarniranta / Cellular Signalling 23 (2011) 747–752
hypoxic induction of MIF expression was dependent on a hypoxia-
responsive element in the MIF promoter. Subsequently, genome-wide
studies have identified MIF as one of the functional HIF-1 target genes
[62]. HIF-1 stimulation can enhance MIF-mediated angiogenesis,
especially in tumorigenesis [21,22]. Interestingly, induction of MIF by
HIF-1 delays the premature senescence induced by p53 activation
[63]. Obviously, there are several other HIF-1 induced activities which
are mediated by the MIF-induced repression of p53 activity (Fig. 1B).
On the other hand, Blagosklonny et al. [64] demonstrated that p53 can
repress HIF-1α -stimulated expression of MIF at the transcriptional
level. Recently, Yamakuchi et al. [65] observed that one of the p53-
induced microRNAs, miR-107, could inhibit the expression of HIF-1β
and subsequently the transcription by the heterodimeric HIF-1α/β
complex. In addition, p53 protein promoted the MDM2-mediated
ubiquitination of HIF-1α and thus its proteasomal degradation [66].
These studies established the negative feedback regulation between
p53 and MIF. It seems that MIF, a pro-inflammatory cytokine, is an
important mediator in the hypoxia-triggered responses via the
repression of p53. The deficiency in the activity of p53, observed in
many polymorphic changes in the TP53 gene [67], can potentiate the
role of hypoxia and HIF-1 regulation in MIF-induced responses e.g. in
glucose metabolism and diabetes [35,36] and systemic inflammation
[37].
MIF is a multifunctional cytokine and several studies have demon-
strated that its expression is under the control of NF-κB signaling
network (Fig. 1B). The MIF promoter contains two functionally active
NF-κB binding sites [68,69]. A number of pro-inflammatory insults,
e.g. IL-1β, TNF-α, and oxidized LDL, can activate the expression of
MIF [68–70]. However, it seems that the MIF promoter is the target of
several transactivation pathways, e.g. hypoxia can activate expression
of MIF via HIF-1 but in a NF-κB-independent manner [71]. On the
other hand, MIF activates the expression of pro-inflammatory factors
via NF-κB signaling pathway [72–74]. Interestingly, it seems that
MIF and NF-κB coordinate their activities via a positive feedback
loop (Fig. 1B). One can postulate that MIF regulates gene expression
via several signaling pathways which are independent on NF-κB
transactivation. In summary, MIF is an important nodal point linking
inflammatory signals with the repression of p53 signaling (Fig. 1B).
Obviously, this regulation is highly tissue-specific and dependent on
several co-factors involved in the network.
4. WIP1 and MIF: regulation of cellular senescence and
organismal aging
The p53 and NF-κB signaling pathways are profoundly involved in
the regulation of cellular senescence and aging process. The p53
pathway is engaged in the triggering of the senescence process in
stressed cells. Subsequently, senescent cells generate a pro-inflam-
matory SASP which includes the signaling via the NF-κB pathway
[6,7]. In the organismal aging, p53 signaling seems to decline since the
efficiency of p53-mediated responses to cellular stresses decreases
during aging [75]. However, an enhanced p53 expression can induce
premature aging in some contexts but delay the aging process in
some animal models [see 76]. In contrast, the aging process itself and
age-related degenerative diseases are associated with the activation
of NF-κB signaling [11,17,18,77]. This is reminiscent of the functional
antagonism between p53 and NF-κB signaling [14] but it is still not
certain that WIP1 and MIF are involved in this reciprocal regulation in
cellular senescence and organismal aging.
WIP1 is located at the crossroads between negative feedback
loops with p53 and NF-κB (Fig. 1A). It seems that this position
of WIP1 provides a possibility to achieve antagonistic regulation
of the p53 and NF-κB pathways, i.e. increased p53 activity inhibits
NF-κB signaling and vice versa. p16INK4a and ARF are activated in
WIP1 null mice (see preceding discussion). These factors are potent
inducers of cellular senescence but they are also upregulated in the
tissues of old mice [78]. The WIP1 null condition enhances the
function of both p53 and NF-κB due to the loss of WIP1-induced
repression in both pathways (Fig. 1A). This situation can support
the cellular senescence and induce the SASP. It is not known
whether or not WIP1 is down-regulated in organismal aging.
Recent evidence indicates that WIP1 could be impaired during
aging in some tissues [20]. WIP1 knockout mice showed a modest
reduction in longevity [79,80]. Moreover, WIP1 null mice exhibited
several defects in T- and B-lymphocyte responses and there was
clear inflammation in several tissues. All these defects emphasize
the overwhelming activity of NF-κB system, as observed in WIP1
null cells [25].
DNA damage has been implicated as one of the factors accelerating
the aging process, e.g. in progeroid syndromes [81]. WIP1 is induced
by p53 but subsequently WIP1 down-regulates intrinsic ATM/ATR-
p53 and p38MAPK-driven DNA damage signaling pathways. Recently,
Zhang et al. [82] demonstrated that DNA damage also induced
the expression of miR-16 which is a miRNA inhibitor of WIP1. This
prevented the premature inactivation of DNA damage repair. The
presence of oxidative stress and age-related genotoxic damage also
imply that WIP1 could be down-regulated during aging. Reduced
WIP1 activity support the HBP1-mediated, Ras-induced premature
senescence [83,84]. This oncogenic type of cellular senescence is
induced by p16INK4a and it is a potent repressor of tumorigenesis.
Reduced WIP1 activity also enforces the p38MAPK-dependent
activities which include p16INK4a-induced cellular senescence and
inflammatory responses [85]. All of these are also present in
organismal aging (see preceding discussion). Moreover, Davis and
Kipling [86] have demonstrated that the inhibition of p38MAPK can
extend the lifespan of Werner syndrome fibroblasts. There are several
age-related diseases, e.g. atherosclerosis, diabetes and osteoporosis,
which are associated with the activation of p38MAPK. In summary,
reduction of WIP1 activity, probably due to the decline in p53 activity,
removes one potent repressor from NF-κB signaling and p38MAPK
activity which accelerates a premature aging process and exposes
tissues to age-related degenerative diseases.
MIF is a pro-inflammatory cytokine which is linked to NF-κB
signaling via a positive feedback loop but it directly inhibits the function
of p53 (Fig. 1B). Interestingly, Harper et al. [87] observed that MIF-
knockout mice clearly lived longer than their control counterparts.
One plausible explanation could be the fact that the aging process is
associated with a low-level inflammation (so-called inflammaging) and
the lack of MIF could down-regulate NF-κB-mediated inflammatory
signaling. Supporting this concept, neutralization of serum MIF is a
promising therapy in several inflammatory disorders [33]. Obesity is
linked to the presence of inflammation in adipose tissues. Interestingly,
human visceral fat depots display a unique profile of inflammatory
mediators compared to subcutaneous adipose tissue, i.e. MIF and
chemokine receptor 2 are clearly overexpressed in visceral fat [88].
Abdominal fat is a stronger risk factor for metabolic disorders and
mortality than subcutaneous fat [89] and in that way visceral MIF could
accelerate aging process. In summary, increased level of MIF can support
inflammatory responses by enhancing NF-κB system and in addition,
repressing the function of p53 which can also enhance inflammatory
responses [19].
HIF-1 is activated in tissue injuries and inflammatory microenvir-
onments [90]. During the aging process, increased inflammation and
degenerative responses in the extracellular space activate NF-κB
signaling and subsequently repress p53 function which alleviates
p53-mediated HIF-1 repression and supports MIF activation (Fig. 1B).
It seems that NF-κB can potentiate the function of MIF both directly
and via the repression of p53. Enhanced MIF expression could inhibit
the function of p53 during aging. In cellular senescence models,
the activation of HIF-1 has been demonstrated to delay premature
senescence via MIF activation [63]. Not surprisingly, this is referred to
the MIF-induced repression of p53 function, since p53 signaling is a
 A. Salminen, K. Kaarniranta / Cellular Signalling 23 (2011) 747–752
major stimulator of cellular senescence although the mTOR pathway
also seems to be involved [91].
MIF occupies a crucial position between p53 and NF-κB signaling in
the regulation of apoptotic cell death. The p53 protein is a potent
inducer of apoptosis whereas NF-κB is a powerful anti-apoptotic
factor. Theoretically, increased MIF expression should prevent apo-
ptosis via the positive loop with NF-κB and the repression of p53. This
seems to be the case, since there is an extensive literature revealing
that MIF induces a strong resistance to apoptosis [92,93] which in
some situations can enhance tumorigenesis [22,93]. MIF interacts
with Bim and inhibits its pro-apoptotic activity [94]. Increased
resistance to apoptosis is a hallmark of cellular senescence [95] and
a deficiency in the apoptotic cleansing of sublethally damaged cells
from tissues could potentiate the organismal aging. MIF can also
induce the retention of p53 within the cytoplasm [60]. Cytoplasmic
p53 is a potent repressor of autophagy [96] and in that way MIF
can inhibit autophagic cleansing of damaged structures. Autophagic
uptake and degradation are clearly repressed during aging [97]. In
addition to inflammatory responses (see earlier discussion), MIF
can also enhance the aging process by inhibiting the apoptotic and
autophagic cleansing processes.
5. Conclusions
The signaling pathways of p53 and NF-κB have a key role in the
regulation of cellular senescence and organismal aging. In several
signaling contexts, these ancient signaling networks display a
functional antagonism inhibiting each others’ activity [14]. Moreover,
they appear to respond to different types of stresses, i.e. intrinsic
stress, e.g. DNA damage, hypoxia and nutrient stress, activates p53
signaling whereas extrinsic stress, e.g. infections, inflammation and
oxidative stress, stimulates the NF-κB system. Both pathways have
common interacting proteins which create a signaling circuitry of
positive and negative autoregulatory loops with p53 and NF-κB. The
partners at the intersections are particularly important since the
crosstalk between p53 and NF-κB can control the specific signaling
responses to a variety of stresses. WIP1 and MIF are good examples of
signaling molecules which link the p53 and NF-κB pathways together
through positive and negative feedback loops.
Organismal aging seems to be associated with a decline in the
efficiency of the p53 signaling pathway. The accumulation of DNA
damage, the increased resistance to apoptosis and the decay in
oxidative respiration all imply that the signaling of p53 may be down-
regulated during aging. On the other hand, there is abundant evidence
that NF-κB signaling is clearly enhanced during the aging process;
either it is a cause of aging itself or a detrimental consequence. In this
respect, it is important to understand the crosstalks of WIP1 and MIF
between p53 and NF-κB signaling. It seems that the activity of WIP1
decreases during aging, probably attributable to a decline in p53
function, which potentiates the activity of p38MAPK and NF-κB
signaling pathways leading to premature cellular senescence and a
low-level chronic inflammation in several tissues. Activation of NF-κB
system augments the activity of MIF which represses the function of
p53. MIF is a multifunctional cytokine which can regulate glucose
homeostasis and in that way aggravate many age-related degenerative
diseases. MIF null mice are healthier and live longer that their normal
counterparts.
In conclusion, the NF-κB–MIF axis is a potent enhancer of
organismal aging; in particular its function at the systemic level
appears to accelerate the aging process and augment age-related
degenerative diseases. A decline in p53 activity might enhance the
process via the inactivation of WIP1. On the other hand, p53 signaling
is a major inducer of cellular senescence, evoking an irreversible arrest
of cell cycle. There are many stress insults which can trigger cellular
senescence in cultured cells but it has been difficult to identify the
hallmarks of cellular senescence in tissues in vivo. Although senescent
751
cells exhibit a pro-inflammatory SASP, the molecular mechanisms of
NF-κB activation in SASP process still need to be established.
Acknowledgments
This study was financially supported by grants from the Academy
of Finland and the University of Eastern Finland, Kuopio, Finland. The
authors thank Dr. Ewen MacDonald for checking the language of the
manuscript.
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