Small Interference RNA-mediated Gene Silencing of Human Biliverdin Reductase, but Not That of Heme Oxygenase-1, Attenuates Arsenite-mediated Induction of the Oxygenase and Increases Apoptosis in 293A Kidney Cells

Abstract

BVR reduces biliverdin, the HO-1 and HO-2 product, to bilirubin. Human biliverdin (BVR) is a serine/threonine kinase activated by free radicals. It is a leucine zipper (bZip) DNA-binding protein and a regulatory factor for 8/7-bp AP-1-regulated genes, including HO-1 and ATF-2/CREB. Presently, small interference (si) RNA constructs were used to investigate the role of human BVR in sodium arsenite (

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

“…[18][19][20][21][22] The contribution of hBVR to antioxidant protection offered by induction of the stress-inducible ho-1 was demonstrated by the observation that inhibition of hBVR, by siRNA treatment potentiates ROS-mediated damage to cells and promotes apoptosis. 23 BVR is known as a biliverdin-converting enzyme; however, recent findings have uncovered additional functions of the human reductase that relate to its kinase activity and reflect its structural features. 24 The S/T/Y (serine/threonine/tyrosine) kinase activity of hBVR has been linked to its function in the insulin/IGF receptor signaling cascade in both the MAPK and PI3K branches, 25,26 and its DNA binding has been shown to involve its bZip domain.…”

“…[27][28][29] hBVR, as with other members of this family of AP-1/CRE binding transcription factors: c-Jun, c-Fos, c-Myc and CREB/ATF-2, is activated by free radicals. Its activation is demonstrably a determining factor in response of ho-1 to oxidative stress 23 and hence bilirubin production and hBVR activation also influence glucose uptake 26 as well as CREB/ATF-2 gene expression. 29 Bilirubin not only participates in defense mechanisms against free radical injury induced by ROS, 19 but serves this function in glucose-induced oxidative injury 30,31 and against nitrosative stress produced by peroxynitrite 32 or nitric oxide.…”

Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling

“…Activation of PKCs and ERK is associated with the induction of AP-1 transcription factors (c-Jun, c-Fos, and ATF-2/CREB), which are downstream targets of MAPK (8). Activation of hBVR has been correlated with the aforementioned AP-1 transcription factor induction and NF-B that acts downstream of the MAPK/PI3K/Aktsignaling cascade (9)(10)(11); the stress-activated enzymes HO-1 and iNOS are among the targets of the transcription factors (12)(13)(14)(15). Moreover, an outcome of ERK activation is cell differentiation and proliferation; notably, the overexpression of hBVR results in a striking change in cell morphology (16).…”

“…The presence of this sequence in the Elk subfamily of ERK substrates ensures high-affinity binding of these proteins to ERK (25). Both hBVR and Elk1 are transcription factors with overlapping target genes: Elk1 is an ETS-domain transcription factor that binds to target promoters after phosphorylation and dissociation from ERK (26), whereas hBVR is a bZip transcription factor and binds to 7/8-bp AP1 sites (10). A comparison of hBVR and Elk1 primary structures is presented in supporting information (SI) Fig.…”

“…Cells were transfected with plasmids, as appropriate, by using Transfectin (Bio-Rad). pSuper-si-hBVR or sc-hBVR were prepared as before (10). Cells were infected with four plaqueforming units per cell.…”