Abstract
Biliverdin reductase (BVR) is a multifunctional protein that is the primary source of the potent antioxidant, bilirubin. BVR regulates activities/functions in the insulin/IGF-1/IRK/PI3K/MAPK pathways. Activation of certain kinases in these pathways is/are hallmark(s) of cancerous cells. The protein is a scaffold/bridge and intracellular transporter of kinases that regulate growth and proliferation of cells, including PKCs, ERK and Akt, and their targets including NF-κB, Elk1, HO-1, and iNOS. The scaffold and transport functions enable activated BVR to relocate from the cytosol to the nucleus or to the plasma membrane, depending on the activating stimulus. This enables the reductase to function in diverse signaling pathways. And, its expression at the transcript and protein levels are increased in human tumors and the infiltrating T-cells, monocytes and circulating lymphocytes, as well as the circulating and infiltrating macrophages. These functions suggest that the cytoprotective role of BVR may be permissive for cancer/tumor growth. In this review, we summarize the recent developments that define the pro-growth activities of BVR, particularly with respect to its input into the MAPK signaling pathway and present evidence that BVR-based peptides inhibit activation of protein kinases, including MEK, PKCδ, and ERK as well as downstream targets including Elk1 and iNOS, and thus offers a credible novel approach to reduce cancer cell proliferation.
Highlights
This in turn led to the observation that BVR is itself a protein kinase (Salim et al, 2001; Lerner-Marmarosh et al, 2005), and that it belongs to the Biliverdin reductase in cancer relatively rare class of dual specificity kinases that phosphorylate tyrosine in addition to serine and threonine
Given the nuclear localization of BVR seen in kidney tumors (Maines et al, 1999), and its ability to activate transcription factors linked to cell growth, this result is a tempting indication of BVR perhaps being directly involved in tumor cell growth
Because Akt phosphorylation was attenuated in cells treated with small interfering RNA (siRNA) directed against BVR, it is likely that BVR is a cytoprotective signaling protein, by virtue of its activation of the phosphatidylinositide 3kinase (PI3K) pathway in response to oxidative stress (Pachori et al, 2007)
Summary
Some 50 years ago, an enzymatic activity that reduced biliverdin to bilirubin was described (Singleton and Laster, 1965; Tenhunen et al, 1970) and subsequently named biliverdin reductase (BVR). The D-Box of human BVR overlaps with a Zn(II) binding cysteine-rich sequence that resembles similar motifs found in the C2 regulatory domains of PKCs (Steinberg, 2008; Newton, 2010). This cysteine-rich sequence has the potential to respond to the redox status of the cell, and could function as a signaling switch, for example in oxidative stress. Two major pathways that regulate cell proliferation survival and invasion, i.e., RasMAPK and PI3K, play central roles in multiple processes in cancer (Malumbres and Barbacid, 2003) Both cascades have input from BVR at multiple steps, and the modes of activation by BVR will be discussed
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