The beginning of GPX2 and 30 years later.

We published the first paper to characterize GPX2 (aka GSHPx-GI) as a selenoenzyme with glutathione peroxidase activity in 1993. Among the four Se-GPX isozymes, GPX1-4, GPX1 and GPX2 are closely related in terms of structure, substrate specificities, and subcellular localization. What sets them apart are distinct patterns of gene regulation, tissue distribution and response to selenium. While we identified the digestive tract epithelium as the main site of GPX2 expression, later work has shown GPX2 is found more widely in epithelial tissues with concentration of expression in stem cell and proliferative compartments. GPX2 expression is regulated over a wide range of levels by many pathways, including NRF2, WNT, p53, RARE and this often results in attaching undue significance to GPX2 as GPX2 is only a part of a system of hydroperoxidase activities, including GPX1, peroxiredoxins and catalase. These other activities may play equal or greater roles, particularly in cell lines cultured without selenium supplementation and often with very low GPX2 levels. This could be assessed by examining levels of mRNA and protein among these various peroxidases at the outset of studies. As an example, it was found that GPX1 responds to the absence of GPX2 in mouse ileum and colon epithelium with higher expression. As such, both Gpx1 and Gpx2 had to be knocked out in mice to produce ileocolitis. However, we note that the actual role of GPX1 and GPX2 in relation to peroxiredoxin function is unclear. There may be an interdependence that requires only low amounts of GPX1 and/or GPX2 in a supporting role to maintain proper peroxiredoxin function. GPX2 levels may be prognostic for cancer progression in colon, breast, prostate and liver, however, there is no consistent trend for higher or lower levels to be favorable. [Display omitted] • GPX2 was discovered by investigators screening human liver cDNA libraries with GPX1 probes. • GPX2 was characterized as a cytoplasmic selenoprotein with GPX activity like GPX1 and high expression in gastrointestinal tract. A role for GPX2 in the crypt/gland regions of the mid-lower GI was indicated by work with GPX1-knockout mice, GPX2-knockout mice and a combination of the lines. • Generally independent regulation and compartmentalization define semi-independent roles for the GPX2 and GPX1 isoenzymes. There is likely interaction in other tissues. • Recent work has broadened the range of tissues with expression with suggestion of impact on tumororigenesis and metastasis. Much work is reported without adequate context for GPX2 as a component of an array of hydroperoxidases and performed under conditions where GPX2 protein levels may be miniscule due to cell line or inadequate selenium. • Possible dominance by GPX2 in basal cell compartments is indicated and represents a possible future direction for GPX2 research. [ABSTRACT FROM AUTHOR]