The second ICK interactor we identified is the protein in literature BAT3 or Scythe or BAG6, whose functional roles are becoming clearer even if its names are not. All three names are common. ICK phosphorylates BAT3 Scythe at T1080 in vitro and in situ. BAT3 functions demands more study. The name Scythe came from ability of the protein to bind reaper in in vitro capture e periments, leading to several reports supporting the idea that BAT3 functions in apop tosis. BAT3, for e ample, can interact with an inter membrane mitochondrial protein apoptosis inducing factor, which seemed to fit the apoptosis function hypothesis. A Deletion of BAT3 does cause lethality and major abnormalities in development, and not surprisingly increased apoptosis in tissues.
This is also consistent, but increased apoptosis may result indi rectly, not because of a proposed model that BAT3 is a direct apoptotic regulator. BAT3 fibroblasts are not very different from wild type fibroblasts in propensity to apoptose e cept to a very few stimuli. BAT3 is not directly functioning in any known apoptosis cascades. A second literature supports function of BAT3 as a co chaperone with Hsp70 and regulation of protein stability and ubiquitin dependent degradation. The kinases ICK, MAK, and MOK bind a chaperone Cdc37 p50, a none clusive partner of Hsp90. Finding many interactions for BAT3 suggests a scaf folding domain. We believe a unifying hypothesis for the defects in development in the BAT3 mouse may come in the future from vigorous study of its nuclear functions. BAT3 contains a nuclear localization sequence.
Recent work establishes that nuclear retention of BAT3 can be dependent upon cellular transformation. In the nucleus, BAT3 and SET1A form a comple with Boris to modulate H3K4 histone dimethylation marks and gene e pression. The latter discovery fits nicely with nuclear localization of BAT3 and transforma tion, abnormalities in development, and the high e pres sion of BAT3 and MAK that occurs during spermatogenesis. H3K and H3K4 methylation interplay to regulate gene activation. Nuclear func tion of BAT3 is also indicated by its requirement for p53 acetylation in response to DNA damage. Certain BAT3 genetic variations are strongly linked to suscepti bility to lung cancer. Conclusion ICK is transcribed from a GC rich promoter that con tains a CpG island, and shares Dacomitinib a bidirectional promoter with FB 9.
A minimal ICK promoter is activated by tran scription factors that regulate pro liferation and differentiation in the intestinal epithelium, motivating additional studies in vivo. Several of the can didate motifs for FO family proteins are conserved between mouse and human. Methods Cell lines All of the cell lines were obtained from the American Type Culture Collection in Manassas, VA e cept the AGS cells. Cells were maintained in flasks in Dul beccos modified Eagles medium supplemented with 5% fetal calf serum in an atmosphere containing 5% CO2.