CDK2, N-CoR, Cyclin D1, CDK4, Ubiquitin, MIF, p27KIP1, NF-kB p50/p65, Glucocorticoids, p27KIP1, Cyclin D2, c-Jun, GRB2, UCHL1, Progesterone, JAB1, Cyclin E, Cyclin D3, Cul1/Rbx1 E3 ligase, NCOA1 (SRC1), JAB1, NF-kB1 (p50), Progesterone receptor, GCR-alpha, CRM1, JNK(MAPK8-10)
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 ( c-Jun ) .
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 JAB1 .
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 GCR-alpha - NCOA1 (SRC1) 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) ) , , .