The transcription factor NF-κB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-κB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras-and TGF-β-dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity. IntroductionCancer development and metastasis are multistep processes that involve local tumor growth and invasion followed by dissemination to and re-establishment at distant sites. The ability of a tumor to metastasize is the major determinant of the mortality of cancer patients. Thus, elucidating the molecular pathways essential for tumor metastasis is of high priority in cancer biology and provides a basis for novel therapeutic targets for the development of antimetastatic cancer treatments.Initially discovered and studied as a major activator of immune and inflammatory functions via its ability to induce expression of genes encoding cytokines, cytokine receptors, and cell-adhesion molecules, the transcription factor NF-κB has recently been implicated in the control of cell proliferation and oncogenesis (reviewed in ref. 1). NF-κB transcription factors bind to DNA as hetero-or homodimers that are composed of five possible subunits in mouse and human (RelA/p65, RelB, p50, and p52). These proteins are characterized by their Rel homology domains, which mediate DNA binding, dimerization, and interactions with inhibitory factors known as inhibitor κB (IκB) proteins. Whereas the Rel/p65 and p50 subunits are ubiquitously expressed, the p52, c-Rel, and RelB subunits are more functionally important in specific differentiated cell types (reviewed in ref.2). In most unstimulated cells, NF-κB dimers are inactive because of association with IκB proteins that mask the

The transcription factor NF-κB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-κB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras-and TGF-β-dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity. IntroductionCancer development and metastasis are multistep processes that involve local tumor growth and invasion followed by dissemination to and re-establishment at distant sites. The ability of a tumor to metastasize is the major determinant of the mortality of cancer patients. Thus, elucidating the molecular pathways essential for tumor metastasis is of high priority in cancer biology and provides a basis for novel therapeutic targets for the development of antimetastatic cancer treatments.Initially discovered and studied as a major activator of immune and inflammatory functions via its ability to induce expression of genes encoding cytokines, cytokine receptors, and cell-adhesion molecules, the transcription factor NF-κB has recently been implicated in the control of cell proliferation and oncogenesis (reviewed in ref. 1). NF-κB transcription factors bind to DNA as hetero-or homodimers that are composed of five possible subunits in mouse and human (RelA/p65, RelB, p50, and p52). These proteins are characterized by their Rel homology domains, which mediate DNA binding, dimerization, and interactions with inhibitory factors known as inhibitor κB (IκB) proteins. Whereas the Rel/p65 and p50 subunits are ubiquitously expressed, the p52, c-Rel, and RelB subunits are more functionally important in specific differentiated cell types (reviewed in ref.2). In most unstimulated cells, NF-κB dimers are inactive because of association with IκB proteins that mask the

The data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.

The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.

SUMMARYNF-κB is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-κB activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-κB, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact with β-TrCP, it involved the stabilization of IκB and reduced nuclear translocation of p65. Interestingly, however, Vpu did not affect casein kinase II-mediated phosphorylation of p65. Lack of Vpu was associated with increased NF-κB activation and induction of interferon and interferon-stimulated genes (ISGs) in HIV-1-infected T cells. Thus, HIV-1 and its simian precursors employ Nef to boost NF-κB activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-κB-dependent expression of ISGs at later stages.