Nuclear factor B (NF B) is a ubiquitously expressed transcription factor that is regulated by the cytoplasmic inhibitor protein I B␣. Biological agents such as tumor necrosis factor ␣ (TNF␣), which activate NF B, result in the rapid degradation of I B␣. Adenoviral-mediated gene transfer of Bcl-2 prevents apoptosis of neonatal ventricular myocytes induced by TNF␣. In view of the growing evidence that NF B may play an important role in regulating apoptosis, we determined whether TNF␣ and Bcl-2 could modulate the activity of NF B in ventricular myocytes. Stimulation of myocytes with TNF␣ resulted in a 2.1-fold increase (p < 0.001) in NF B-dependent gene transcription and nuclear DNA binding. Similarly, a 1.9-fold increase (p < 0.0002) in NF B-dependent gene transcription was observed in myocytes expressing Bcl-2. Nuclear DNA binding activity of NF B was significantly increased in myocytes expressing Bcl-2, with a concomitant reduction in I B␣ protein level. The Bcl-2-mediated loss of I B␣ could be prevented by the proteasome inhibitor lactacystin, consistent with the notion that the targeted degradation of I B␣ consequent to overexpression of Bcl-2 utilizes the ubiquitin-proteasome pathway. This was further tested in human 293 cells in which the N-terminal region of I B␣ was identified to be an important regulatory site for Bcl-2. Deletion of this region or a serine to alanine substitution mutant at amino acids 32 and 36, which are defective for both phosphorylation and degradation, were more resistant than wild type I B␣ to the inhibitory effects of Bcl-2. To our knowledge, this provides the first evidence for the regulation of I B␣ by Bcl-2 and suggests a link between Bcl-2 and the NF B signaling pathway in the suppression of apoptosis.The nuclear factor B (NF B) 1 was first identified as a key regulatory molecule necessary for the activation of B lymphocytes gene transcription (1, 2). Because of these initial observations, it is now widely appreciated that NF B is a ubiquitously expressed transcription factor involved in the activation of genes associated with inflammation, cell adhesion, and viral gene transcription (reviewed in Refs. 3 and 4). NF B belongs to a family of transcription factors with Rel homology and include Rel-A, c-Rel, RelB, and Drosophilia dorsal proteins (5-7). The predominant form of NF B exists in mammalian cells as a heterodimeric complex of 50-kDa and 65-kDa/ RelA protein subunits (8 -10). NF B activity can be induced in a number of cell types by a variety of agents, including ionizing radiation, phorbol esters, and proinflammatory cytokines such as interleukin-1 and tumor necrosis factor alpha (TNF␣) (11,12).In contrast to other transcription factors that are typically located within the nucleus of the cell, NF B is sequestered in the cytoplasm by the inhibitor protein I B␣ (5, 13-15). I B␣ prevents the nuclear targeting of NF B by interaction via its conserved ankyrin repeats (7,16,17).The mechanism by which biological signals activate NF B in vivo remains elusive; however, recent stud...
Nuclear factor-kappa B (NF-kappa B) is a ubiquitously expressed cellular factor regulated by the cytoplasmic factor inhibitor protein kappa B alpha (I kappa B alpha). Activation of NF-kappa B by cytokines, including tumor necrosis factor-alpha (TNF-alpha), requires the phosphorylation and degradation of I kappa B alpha. An anti-apoptotic role for NF-kappa B has recently been suggested. In the present study, we ascertained whether death-promoting signals and apoptosis mediated by TNF-alpha are suppressed by NF-kappa B in postnatal ventricular myocytes. Stimulation of myocytes with TNF-alpha resulted in a 12.1-fold increase (P < 0.01) in NF-kappa B-dependent gene transcription and DNA binding compared with controls. This was accompanied by a corresponding increase in the NF-kappa B target protein A20 as determined by Western blot analysis. Vital staining revealed that TNF-alpha was not cytotoxic to myocytes and did not provoke apoptosis. Adenovirus-mediated delivery of a nonphosphorylatable form of I kappa B alpha to inactivate NF-kappa B prevented TNF-alpha-stimulated NF-kappa B-dependent gene transcription and nuclear NF-kappa B DNA binding. Importantly, myocytes stimulated with TNF-alpha and defective for NF-kappa B activation resulted in a 2.2-fold increase (P < 0.001) in apoptosis. To our knowledge, the data provide the first indication that a functional NF-kappa B signaling pathway is crucial for suppressing death-promoting signals mediated by TNF-alpha in ventricular myocytes.
There exists strong evidence that interdisciplinary stroke rehabilitation leads to better functional outcome than does usual care.3 Although there is less evidence regarding the timing of rehabilitation, the need for such services must be determined during acute care to avoid missing this important component of overall stroke care.We therefore propose that an additional indicator be included for optimal stroke care: timely assessment for rehabilitation when appropriate.
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