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Immune response MIF-JAB1 signaling

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Immune response MIF-JAB1 signaling

MIF-JAB1 signaling

Macrophage migration inhibitory factor ( MIF ) is a pluripotent cytokineinvolved in inflammation and immune responses as well as in growth factor-dependent cellproliferation, cell cycle, angiogenesis, and tumorigenesis [1], [2], [3], [4].

Cells may take up MIF by endocytosis. The endocytosis can only occur when theconcentration 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 -dependentcell-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 ( c-Jun ) [5].

JAB1 is a negative regulator of p27KIP1 by promoting its degradation viathe ubiquitin/proteasome pathway mediated by Ubiquitin carboxyl-terminal esterase L1 (UCHL1 ) and Ubiquitin Cul1/Rbx1 E3 ligase complex [6], [7], [8]. p27KIP1 binds to and prevents the activation ofCyclin 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 [9], [10], [11]. The degradation of p27KIP1, which istriggered by its CDK2 dependent phosphorylation and subsequent ubiquitination, isrequired for the cellular transition from quiescence to the proliferative state [12].

JAB1 is the fifth component of the COP9 signalosome complex. At least twodifferent forms of JAB1 -containing complexes exist within the cell: one islocated 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 betweenp27KIP1 and CRM1 to induce p27KIP1 nuclear export and its subsequentdegradation [13]. The cytoplasmic location of p27KIP1 alone is notsufficient for induction of p27KIP1 degradation. Growth factor receptor-boundprotein 2 ( GRB2 ) directly binds to p27KIP1 in the cytoplasm and isrequired for efficient degradation of p27KIP1 [14].

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. MIFinhibits these effects of JAB1 [5].

In the nucleus, JAB1 acts as a special regulator of c-Jun, Nuclearfactor kappa-B ( NF-kB p50/p65 ) and nuclear receptors, such as Glucocorticoidreceptor ( GCR-alpha ) and Progesterone receptor. JAB1 selectivelypotentiates c-Jun transactivation and specifically stabilizes c-Jun-containingAP-1 transcription complexes involved in inducing cell growth and proliferation [15], [5]. JAB1 also directly interacts with Progesteronereceptor, GCR-alpha, and the Nuclear receptor coactivator 1 ( NCOA1(SRC1) ). In the absence of hormone, nuclear receptors repress transcription oftarget genes via interactions with corepressors, such as Nuclear receptor co-repressor 1( N-CoR ). Upon binding of hormone, these corepressors dissociate away from theDNA-bound receptor that subsequently recruits coactivators. JAB1 stabilizesProgesterone receptor - NCOA1 (SRC1) and GCR-alpha - NCOA1(SRC1) complexes, potentiating their transcriptional activity [16].JAB1 also participates, at least partially, in NF-kB p50/p65 regulatedcasacades, through NCOA1 (SRC1) that directly interacts with NF-kB subunit p50 (NF-kB1 (p50) ) [17], [18], [16].