Macrophage migration inhibitory factor (MIF) is a
pluripotent cytokine involved in inflammation and immune responses as well as in growth
factor-dependent cell proliferation, cell cycle, angiogenesis, and tumorigenesis , , , .
Cells may take up MIF by endocytosis. The endocytosis can
only occur when the concentration of MIF in the
extracellular region is very high. Inside cells, MIF
interacts with COP9 constitutive photomorphogenic homolog subunit 5
(JAB1) and deactivates it. MIF
antagonizes JAB1-dependent cell-cycle regulation by
stabilization of Cyclin-dependent kinase inhibitor 1B
(p27KIP1) and inhibits
JAB1-enhanced activity of transcription factors, such as
subunit of the activator protein 1 (AP-1) Jun oncogene
JAB1 is a negative regulator of
p27KIP1 by promoting its degradation via the
ubiquitin/proteasome pathway mediated by Ubiquitin carboxyl-terminal esterase L1
(UCHL1) and Ubiquitin Cul1/Rbx1 E3
ligase complex , , .
p27KIP1 binds to and prevents the activation of Cyclin
E1 (Cyclin E) -
Cyclin-dependent kinase 2
(CDK2) or Cyclin D (Cyclin
D1, Cyclin D2, Cyclin
D3) - Cyclin-dependent kinase 4 (CDK4)
complexes, and thus controls the cell cycle progression at G1 , , . The degradation of p27KIP1,
which is triggered by its CDK2 dependent phosphorylation and
subsequent ubiquitination, is required for the cellular transition from quiescence to the
proliferative state .
JAB1 is the fifth component of the COP9 signalosome
complex. At least two different forms of JAB1-containing
complexes exist within the cell: one is located in the nucleus, and the other is mainly
located in the cytoplasm. In the nucleus, JAB1 interacts
with Exportin 1 (CRM1) and functions as an adaptor between
p27KIP1 and CRM1 to induce
p27KIP1 nuclear export and its subsequent
degradation . The cytoplasmic location of
p27KIP1 alone is not sufficient for induction of
p27KIP1 degradation. Growth factor receptor-bound protein 2
(GRB2) directly binds to
p27KIP1 in the cytoplasm and is required for efficient
degradation of p27KIP1 .
JAB1 also enhances Mitogen-activated protein kinases 8-10
(JNK(MAPK8-10)) activity. This increases the phosphorylation
level of c-Jun, and directly potentiates the activities of
several transcription factors. MIF inhibits these effects of
In the nucleus, JAB1 acts as a special regulator of
c-Jun, Nuclear factor kappa-B (NF-kB
p50/p65) and nuclear receptors, such as Glucocorticoid receptor
(GCR-alpha) and Progesterone
receptor. JAB1 selectively potentiates
c-Jun transactivation and specifically stabilizes
c-Jun-containing AP-1 transcription complexes involved in inducing cell growth and
proliferation , . JAB1 also
directly interacts with Progesterone receptor,
GCR-alpha, and the Nuclear receptor coactivator 1
(NCOA1 (SRC1)). In the absence of hormone, nuclear receptors
repress transcription of target genes via interactions with corepressors, such as Nuclear
receptor co-repressor 1 (N-CoR). Upon binding of hormone,
these corepressors dissociate away from the DNA-bound receptor that subsequently recruits
coactivators. JAB1 stabilizes Progesterone
receptor-NCOA1 (SRC1) and
complexes, potentiating their transcriptional activity .
JAB1 also participates, at least partially, in
NF-kB p50/p65 regulated casacades, through
NCOA1 (SRC1) that directly
interacts with NF-kB subunit p50 (NF-kB1 (p50)) , , .
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