Interleukin-1 (IL-1), a proinflammatory cytokine produced mainly by macrophages and monocytes in response to inflammation, infection, and other challenges, stimulates a wide spectrum of responses, including fever, lymphocyte activation, and leukocyte infusion to the site of injury or infection (16). IL-1 stimulates the expression of several genes by activating the transcription factors NF-B, ATF, and AP-1 (6, 51, 52).The activation of NF-B has been studied extensively (4, 6, 16). NF-B is kept in the cytoplasm through interaction with B inhibitory proteins. Following stimulation with cytokines (e.g., IL-1 and tumor necrosis factor alpha [TNF-␣]) or other agents (e.g., lipopolysaccharide, phorbol ester, and doublestranded RNA), IB undergoes phosphorylation on specific serine residues and is rapidly ubiquitinated and degraded. The liberated NF-B translocates to the nucleus, where it activates transcription (5,63,66,69). Recent studies have provided a model for how NF-B is activated in response to IL-1 (Fig. 1). First, a complex is formed between the type 1 receptor (IL-1R1) and the receptor accessory protein (IL-1RAcP) (21, 24, 29, 70). The cytosolic myeloid differentiation protein (MyD88) (36) is then recruited to the complex, where it functions as an adaptor, recruiting IL-1R-associated kinase (IRAK) in turn (10,48,71,75). IRAK is phosphorylated and then leaves the receptor complex to interact with TRAF6 (11). IRAK2, an IRAK homolog, was shown to interact with the IL-1R complex, MyD88, and TRAF6 in transfected cells, but how IRAK and IRAK2 function in IL-1 signaling is not understood (48). Six TRAFs (TNF receptor-associated factors) have been described so far (2,17,22,23,25,31,49,58). TRAF2 and TRAF5 have been implicated in activating NF-B in response to the activation of members of the TNF-␣ receptor superfamily (2,17,22,23,25,31,49,58). The TRAFs interact with NF-Binducing kinase (NIK), another serine-threonine kinase believed to be a common downstream component in activating NF-B in response to IL-1, TNF-␣, and other stimuli (41). TRAFs might also activate mitogen-activated protein kinase/ ERK kinase kinase 1 (MEKK1) (30,32,35,64,76). Recently, two IB kinases (IKK␣ and IKK␤) have been implicated in signal-induced phosphorylation of the IB proteins (15,44,57,73,78). Both NIK and MEKK1 activate the IKKs by serine phosphorylation (34, 50). The activated IKKs then phosphorylate IBs on specific serine residues, resulting in the degradation of IB and activation of NF-B. The IKKs are components of a large complex (15,44,78). Two additional components, NEMO (NF-B essential modulator or IKK␥) and IKAP are also part of the IKK complex and are required for its formation (12,59,74).Recent studies provide evidence for a second signaling pathway parallel to the cascade leading to IB degradation and specifically required for NF-B-dependent transcriptional competency (Fig.

The rat cell line REF52 is not permissive for gene amplification. Simian virus 40 tumor (T) antigen converts these cells to a permissive state, as do dominant negative mutants of p53, suggesting that the effect of T antigen is due mainly to its ability to bind to p53. To manipulate permissivity, we introduced a temperature-sensitive mutant of T antigen (tsA58) into REF52 cells and selected for resistance to

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