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_6 label "Selventa" provenance.
_5 value "The ability of BVR to activate expression of these genes was established in 293A cells from human embryonic kidney transfected with an adenoviral construct containing BVR. BVR is a bzip-type transcription factor that binds in dimeric form to AP-1 sites. Activation of AP-1 is the key event in oxidative stress response of ho-1 and other stress proteins (54). BVR regulates cellular levels of biliverdin, a potent gene regulator as illustrated by its being the determinant factor for dorsal axis development in Xenopus larva, by the suppression of PKC isozymes, by inhibition of BVR binding to AP-1 regulatory elements in the promoter of ho-1, and by activation of Ah receptor (1, 14, 41, 50). On an equimolar basis (50 uM), biliverdin is as potent an inhibitor of PKC (alpha, beta, gamma, mixture) as a commercially available PKC inhibitory peptide (RKRCLRRL). At this concentration, biliverdin inhibits PKC activity by 95%; bilirubin, a known inhibitor of PKC (19), causes 50% inhibition of PKC activity. The occurrence of a regulatory loop in the cell to control the heme degradation activity of HO-1, which would involve a combination of negative product-feedback processes, i.e., inhibition of heme oxidation by biliverdin and reduction of the latter by bilirubin (26, 27)-in other words, coupled catalytic activity of BVR and HO-1-can be considered. HO-1 is an early-response oxidative-stress gene. BVR is also activated by oxidants (33, 41, 51). Accelerated rate of conversion of biliverdin to bilirubin, i.e., inactivation of biliverdin, allows for induction of ho-1 expression and increased hemedegradation activity (26); the subsequent negative feedback inhibition of BVR activity by its product (bilirubin) would allow for buildup of biliverdin levels, causing product (biliverdin) inhibition of the oxygenase, hence permitting a return to normal conditions of the heme degradation (27). A direct link between BVR and the ho-1 oxidative-stress response became evident by attenuated responses of ho-1 to superoxide anion and arsenite in cells treated with antisense BVR or small interference (si) BVR (1, 41). In real-life settings, BVR activity may become crucial to survival. For instance, under hemolytic conditions or induction of ho-1 expression, a large amount of heme is degraded, requiring high levels of BVR to prevent biliverdin levels from rising beyond normal physiological levels. If not available, then the fatal \"green jaundice\" would occur (18). Biliverdin, unlike bilirubin, is not lipophilic and does not cross the cell membrane lipid bilayer. In fact, in earlier days, BVR was considered to be specific to placental animals, allowing elimination of the heme degradation product from the fetus. The fatality could reflect both an attenuated immune and oxidative stress response for induction of cytoprotective genes and the deficiency in production of bilirubin, a potent antioxidant in the cell (57). It is relevant that exceedingly high concentrations of biliverdin can accumulate as a consequence of exposure to compounds that disrupt cell-signaling pathways (31). A second mechanism by which BVR is likely to affect ho-1 gene expression would involve its heterodimerization with other members of the bzip family of transcription factors, such as c-Jun, c-Fos, ATF-2/CREB, Myc, and Bach-1; all are able to form heterodimeric complexes. The bzip motif of BVR is involved in DNA binding (1). BVR is a regulator of cjun and atf-2/creb gene expression (25). In the case of ATF-2, when its levels are increased, it effectively competes with c-Fos, the usual dimer partner of c-Jun. The ATF-2/c-Jun heterodimer preferentially binds to the seven-base AP-1 sites (TGACTCA) rather than the usual site of ATF-2, CRE (TGACNTCA). The ATF-2/c-Jun dimer DNA complex is more stable than the c-Fos/c-Jun DNA complex. Moreover, heterodimerization not only alters ATF-2 binding with remarkable variation in affinity for different AP-1/..." provenance.
_5 wasQuotedFrom 16287987 provenance.
assertion hadPrimarySource 16287987 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
assertion wasDerivedFrom _5 provenance.
large_corpus.bel authoredBy _6 provenance.
large_corpus.bel version "1.4" provenance.