A S Baldwin

The abilities of NF-κB to promote cell proliferation, suppress apoptosis, promote cell migration, and suppress differentiation apparently have been co-opted by cellular and viral oncoproteins to promote oncogenesis (Figure ​(Figure2).2). Direct evidence, using both in vitro and in vivo models, indicates that NF-κB is required for oncogenesis, probably at multiple levels. NF-κB likely plays an important role in the early events of oncogenesis, possibly functioning primarily in protecting against transformation-associated apoptosis. In most late-stage tumor cells, classic NF-κB (the p50-p65 heterodimer) is clearly not the only survival factor, because its inhibition does not induce apoptosis in many of these tumor cells. This observation suggests that other events have occurred to upregulate NF-κB–independent cell survival pathways. However, clearly some cancer cells depend on NF-κB for their survival. NF-κB also can contribute to cell progression by transcriptionally upregulating cyclin D1 with corresponding hyperphosphorylation of the tumor suppressor protein Rb. The induction of NF-κB–controlled proliferation may correlate with loss of differentiation in certain settings (47), which may promote oncogenesis. NF-κB is known to regulate certain genes associated with metastasis, such as matrix metalloproteinase 9, tissue plasminogen activator, and ICAM-1. Thus, a more relevant role for NF-κB in later-stage oncogenesis may be to promote metastasis and angiogenesis. Although many tumor cells display some level of constitutive nuclear NF-κB, higher levels of NF-κB and the transcriptional potential of NF-κB can be further enhanced in response to certain types of chemotherapy. Consistent with this, inhibition of NF-κB in parallel with certain (but apparently not all) chemotherapy treatments strongly enhances the apoptotic potential of the chemotherapy. This observation indicates that NF-κB plays an important role in inducible chemoresistance and establishes NF-κB inhibition as a new adjuvant approach in chemotherapy.

Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table ​(Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.

NF-kappa B is an inducible transcription factor comprised of a 50-kD (p50) and a 65-kD (p65) subunit. Induction of NF-kappa B activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, I kappa B, followed by translocation of the active transcription factor complex into the nucleus. Earlier studies suggested that I kappa B targets the p65 subunit of NF-kappa B. However, we demonstrate by in vitro and in vivo methods that the recently cloned I kappa B/MAD-3 interacts with both the p50 and p65 subunits of NF-kappa B, as well as c-Rel. Furthermore, an alternatively spliced, dimerization-deficient transforming variant of p65 (p65 delta) interacts extremely weakly with I kappa B/MAD-3, suggesting that dimerization is important for interaction. We demonstrate that the conserved nuclear localization sequences (NLSs) of NF-kappa B and c-Rel are the targets for I kappa B/MAD-3 interaction. Indirect immunofluorescence experiments demonstrate that I kappa B/MAD-3 expression retains both p65 and p50 in the cytoplasm. Furthermore, and most important, a p65 that contains an SV40 large T antigen NLS in addition to its own NLS is no longer retained in the cytoplasm in the presence of I kappa B/MAD-3. We propose that I kappa B/MAD-3 masks the NLSs of NF-kappa B and c-Rel and that this constitutes the mechanism for cytoplasmic retention of these proteins.