Bomapin is a redox-sensitive nuclear serpin that affects responsiveness of myeloid progenitor cells to growth environment

Abstract

BackgroundHaematopoiesis is a process of formation of mature blood cells from hematopoietic progenitors in bone marrow. Haematopoietic progenitors are stimulated by growth factors and cytokines to proliferate and differentiate, and they die via apoptosis when these factors are depleted. An aberrant response to growth environment may lead to haematological disorders. Bomapin (serpinb10) is a hematopoietic- and myeloid leukaemia-specific protease inhibitor with unknown function.ResultsWe found that the majority of naturally expressed bomapin was located in the nucleus. Both the natural and recombinant bomapin had a disulfide bond which linked the only two bomapin cysteines: one located in the CD-loop and the other near the C-terminus. Computer modelling showed that the cysteines are distant in the reduced bomapin, but can easily be disulfide-linked without distortion of the overall bomapin structure. Low-level ectopic expression of bomapin in bomapin-deficient K562 cells resulted in about 90% increased cell proliferation under normal growth conditions. On the other hand, antisense-downregulation of natural bomapin in U937 cells resulted in a decreased cell proliferation. Bomapin C395S mutant, representing the reduced form of the serpin, had no effect on cell proliferation, suggesting that the disulfide bond-linked conformation of bomapin is biologically important. The bomapin-dependent effect was specific for myeloid cells, since ectopic expression of the serpin in HT1080 cells did not change cell proliferation. In contrast to the survival-promoting activity of bomapin in cells cultured under optimal growth conditions, bomapin enhanced cell apoptosis following growth factor withdrawal.ConclusionsWe propose that bomapin is a redox-sensitive nuclear serpin that augments proliferation or apoptosis of leukaemia cells, depending on growth factors availability.

Toll pathway is required for wound-induced expression of barrier repair genes in the Drosophila epidermis

“…The calcium flash in Drosophila epidermal cells nearby laser or puncture wound sites persists for only 10-50 min (24) (also see Materials and Methods), but might trigger a more stable expression pattern of wound repair gene expression through a Dif-dependent autoregulatory circuit, because both dorsal and Dif genes are transcriptionally activated in epidermal cells around wound sites (20). A serpin (serine protease inhibitor) is a possible candidate for the role of a redox sensor in this pathway, because some serpins have cysteines that are redox sensitive (32,33).…”

“…The loss of Toll pathway components does not result in a complete loss of wound gene transcription, because there is at least one other signaling pathway acting in parallel that also has a combinatorial role in helping to activate wound gene transcription. One such pathway involves the Stitcher receptor tyrosine kinase, the downstream effectors Src42A, DRK, and ERK, and the transcription factor Grainy head (GRH) (11,12,32,33,54).…”

S-Glutathionylated Serine Proteinase Inhibitors as Plasma Biomarkers in Assessing Response to Redox-Modulating Drugs

“…In this context, serpin S -glutathionylation may have a mechanistic connection with the in vivo myeloproliferative activity of NOV-002 (13). The redox-sensitive serpin, bomapin, is directly involved in the responsiveness of myeloid progenitor cells to their microenvironment (29). Posttranslational regulation of serpins in the peripheral circulation may indicate a role in the control of proteolytic pathways.…”

Causes and Consequences of Cysteine S-Glutathionylation

“…As such, serpin S-glutathionylation may predict marrow response to myeloproliferative agents. Inhibition of disulfide bond formation in the redox-sensitive serpin bomapin directly affects the responsiveness of myeloid progenitor cells to their microenvironment (90). Further evaluation of protein S-glutathionylation in a therapeutic setting may provide the sort of biomarkers that are important in drug development and optimization of treatment strategies.…”