The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-kappa B activation through tyrosine phosphorylation but not degradation of I kappa B-alpha. Pervanadate-induced I kappa B-alpha phosphorylation and NF-kappa B activation required expression of the T cell tyrosine kinase p56ick. Reoxygenation of hypoxic cells appeared as a physiological effector of I kappa B-alpha tyrosine phosphorylation. Tyrosine phosphorylation of I kappa B-alpha represents a proteolysis-independent mechanism of NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase.

Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

Tumor necrosis factor-␣ (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-B (NF-B). NF-B is

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-κB (NFκB). We investigated the effect of NGF on the expression of Bcl-xL, an anti–apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1–10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFκB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFκB p65 subunit. NGF-induced NFκB activity and Bcl-xL expression were inhibited in cells overexpressing the NFκB inhibitor, IκBα. Unlike tumor necrosis factor-α (TNF-α), however, NGF-induced NFκB activation occurred without significant degradation of IκBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged IκBα. Moreover, in contrast to TNF-α, NGF failed to phosphorylate IκBα at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IκBα potently suppressed NFG-, but not TNF-α–induced NFκB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-α–, but not NGF-induced NFκB activation. We conclude that NGF and TNF-α induce different signaling pathways in neurons to activate NFκB and bcl-x gene expression.