Functional Association of Nmi with Stat5 and Stat1 in IL-2- and IFN γ-Mediated Signaling

Abstract

Using the coiled-coil region of Stat5b as the bait in a yeast two-hybrid screen, we identified the association of Nmi, a protein of unknown function previously reported as an N-Myc interactor. We further show that Nmi interacts with all STATs except Stat2. We evaluated two cytokine systems, IL-2 and IFNgamma, and demonstrate that Nmi augments STAT-mediated transcription in response to these cytokines. Interestingly, Nmi lacks an intrinsic transcriptional activation domain; instead, Nmi enhances the association of CBP/p300 coactivator proteins with Stat1 and Stat5, and together with CBP/p300 can augment IL-2- and IFNgamma-dependent transcription. Therefore, our data not only reveal that Nmi can potentiate STAT-dependent transcription, but also suggest that it can augment coactivator protein recruitment to at least some members of a group of sequence-specific transcription factors.

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

“…52 The PPARs have been implicated in a wide range of biological processes, including cell growth, lipid homeostasis, apoptosis and inflammation. 53 Notably, an additional transcriptional co-activator, NMI, which interacts with all STATs (except STAT2) and potentiates their association with the coactivators CBP/p300 54 was upregulated in all three strains by 3 h IFN-a stimulation and significantly overexpressed in MRL/lpr and BALB/c mice at 3 h time point. Interestingly, NMI and CITED2 exhibited different responses to IFN-a treatment in two lupus-prone strains.…”

STAT3-mediated differentiation and survival of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27Kip1

“…Suggestive of such an alteration, it is noteworthy that the electrophoretic mobility of STAT3 complexes consistently decreased after 3 days of culture (Figure 1). Recently, it was shown that the N-Myc interactor (Nmi) protein associates with di erent STAT proteins, including STAT3, and augments STAT-induced transcription by enhancing recruitment of the coactivator proteins CBP/p300 (Zhu et al, 1999). The fact that Nmi expression is induced by multiple cytokines provides a novel mechanism for speci®c enhancement of STAT transcriptional activity by growth factors, including G-CSF, which may be relevant in this context.…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…For instance, Sp1 has been reported to interact with Stat1 (Look et al, 1995), cJun with Stat3b (Schaefer et al, 1995), MCM5 with Stat1a (Zhang et al, 1998a), and the glucocorticoid receptor with Stat3, Stat5a, and Stat5b (Cella et al, 1998;Stocklin et al, 1996;Zhang et al, 1997). In addition, coactivators CBP/p300 have been shown to interact with Stat1, Stat2, Stat5a, Stat5b and Stat6 (Bhattacharya et al, 1996;Gingras et al, 1999;P®tzner et al, 1998;Zhang et al, 1996;Zhu et al, 1999). Nmyc interacting protein (Nmi) was shown to associate with Stat5b in a yeast two-hybrid interaction trap and by coprecipitation (Zhu et al, 1999).…”

“…In addition, coactivators CBP/p300 have been shown to interact with Stat1, Stat2, Stat5a, Stat5b and Stat6 (Bhattacharya et al, 1996;Gingras et al, 1999;P®tzner et al, 1998;Zhang et al, 1996;Zhu et al, 1999). Nmyc interacting protein (Nmi) was shown to associate with Stat5b in a yeast two-hybrid interaction trap and by coprecipitation (Zhu et al, 1999). The exact mechanism(s) by which these transcription factors and coactivators integrate their e ects into the signals mediated by STAT proteins require further work, but it seems that ubiquitously expressed coactivators CBP/ p300 are generally important for STAT-mediated transcription.…”