The Interferon-Inducible p202 Protein as a Modulator of Transcription: Inhibition of NF-κB, c-Fos, and c-Jun Activities

Abstract

The interferons (IFNs) are cytokines with antiviral, antibacterial, antiprotozoal, immunomodulatory, and cell growth-regulatory functions. They exert these functions by controlling the expression of numerous genes encoding effector proteins (16,41,55,65). One set of effector proteins, including p202, p203, p204, and D3, is encoded by six or more structurally related and IFN-activatable murine genes at the q21-q23 region of chromosome 1 (gene 200 cluster) (13,36,42,48,59). Two homologous human proteins (myeloid cell nuclear differentiation antigen [MNDA] and IFI16) have also been described (7, 64). The proteins encoded by all these genes have homologous C-terminal 200-amino-acid segments (42).At least four of the proteins (p202, p204, MNDA, and IFI16) are nuclear (7,11,12,15,42). Upon treatment of cells with IFN, the induced p202 first appears in the cytoplasm, where it is attached to a fast-sedimenting subcellular component, and then accumulates in the nucleus after a delay (12). In metaphase cells, p202 appears to be associated with chromatin. Although p202 binds DNA in vitro, the cleavage of DNA in isolated nuclei does not result in the release of p202. This and other results suggest that the binding of p202 in the nucleus is at least in part due to protein-protein interactions.The proteins found to bind to p202 in vitro and in vivo include the retinoblastoma susceptibility protein pRb (10), which has a central role in controlling cell cycling (68). It is the hypophosphorylated, growth-inhibitory form of pRb that binds to p202. Overexpression of p202 in transfected cells slows down cell proliferation. The contribution of the interaction between p202 and pRb to the cell growth-inhibitory activity of p202 remains to be explored. However, the finding that p202 interacts with pRb prompted us to test whether p202 also interacts with other proteins controlling transcription. Here we describe studies concerning the effect of p202 on the NF-B p50 and p65 and the AP-1 c-Jun and c-Fos transcription factors. (5,56,57,60). The NF-B protein is a heterodimer consisting of two proteins, p50 (also designated NF-B 1 ) and p65 (also designated Rel A). p50 and p65 are members of the Rel/NF-B family of proteins. These proteins serve as inducible eukaryotic transcription factors that form various homo-and heterodimers. NF-B (i.e., the p50-p65 complex) is present in essentially all cells and is the most abundant of the Rel/NF-B family heterodimers. NF-B is retained in an inactive form in the cytoplasm as a consequence of the binding of particular proteins of the IB family (6, 24) (i.e., IB-␣ and IB-␤) (62). The activation of NF-B and its movement to the nucleus can be correlated with the proteolytic degradation of one or both of the IB proteins (8,46,49,60,62,63). This can be triggered by the phosphorylation of these proteins. The long list of agents activating NF-B includes various cytokines (e.g., interleukin-1 and tumor necrosis factor alpha), phorbol esters (e.g., phorbol myristate acetate [PMA] and tetradecanoyl phorbol ace...

pRB is required for interferon-γ-induction of the MHC class II Aβ gene

“…In this model, pRB would be required to antagonize the inhibitor. One protein that could ful®ll this role is p202; it is induced by IFNs, acts as a transcriptional repressor, and interacts directly with pRB (Choubey and Lengyel, 1995;Choubey et al, 1996;Min et al, 1996). The inhibitor could also be a protein like PU.1, which speci®cally represses Ab expression by binding an element next to the Y box, and also interacts with pRB (Borras et al, 1995;Hagemeier et al, 1993).…”

The IFN-inducible nucleoprotein IFI 16 is expressed in cells of the monocyte lineage, but is rapidly and markedly down-regulated in other myeloid precursor populations

“…The expression of these molecules is limited to a few tissues, including subsets of hematopoietic cells and fibroblasts [40], and each is expressed in the nucleus either constitutively or inducibly after addition of IFN-␣ or -␥ [40]. The binding of p202 to cell growth regulatory proteins pRb [21] and p53 [22], and its ability to inhibit transcriptional activation through E2F [23], NF-B, c-Jun, and c-Fos [24] are clear evidence of a role in modulation of a number of generic transcriptional systems. We now have ample evidence that IFI 16 has similar properties in that it can act as a powerful transcriptional repressor in certain model systems in vitro, can bind to pRb, p53, c-Fos but not c-Jun both in vitro and in vivo, and can regulate the cell cycle [unpublished results].…”

“…The effect of p202 on transcription mediated by pRb remains to be elucidated, however, p202 can modulate E2F-mediated transcriptional activation by inhibiting sequencespecific DNA binding by E2F [23]. p202 can also associate with other growth regulatory proteins such as nuclear factor B (NF-B), c-Jun, and c-Fos both in vitro and in vivo, and can inhibit the transcriptional activity of these proteins by inhibiting their binding to DNA [24].…”

A compass that points to lupus: genetic studies on type I interferon pathway

“…47 IFI202 is a transcription factor that influences proliferation, survival and differentiation of B cells and induced by both IFNa and IFNg. 48 Such an example indicates the need to investigate human IFN-inducible genes as well as genes in its signaling pathway as candidates for susceptibility genes to human SLE.…”