More than 50 genes of the bacterial genetic reservoir are required for motility and chemotaxis. These genes are strictly regulated by a hierarchy of transcription controls that determine the temporal order of flagellar assembly, motility, and chemotaxis, as has been intensely studied in enterobacteria, such as Escherichia coli and Salmonella enterica serovar Typhimurium (1, 31, 56). The E. coli flagella, motility, chemotaxis, and regulatory genes map in four separate clusters referred to as the flagellar regulon. These have been assigned to three sequentially expressed classes. Class I comprises two genes, flhD and flhC, encoding the global transcriptional activator FlhD 2 FlhC 2 . This, in turn, regulates the expression of class II genes, including determinants of the flagellar basal body, the flagellin-specific type III export, the flagellar hook, and FliA, a 28 ( F ) transcription factor for class III. This ultimate class contains the fla (flagellin), mot (proton channel), and che (signal transduction) genes.The nitrogen-fixing plant symbiont Sinorhizobium meliloti, a member of the ␣ subgroup of proteobacteria (38), differs from the enterobacterial ␥ subgroup behavioral scheme in its filament structure, the mode of flagellar rotation, and steps of signal procession (49). The rigid "complex" flagellar filaments consist of four related flagellin subunits, and interflagellin bonds lock the filaments in right-handedness (7,20,48). Hence, S. meliloti cells are propelled by exclusively clockwiserotating flagella, and swimming cells respond to tactic stimuli by modulating their rotary speed (2, 47). Whereas in E. coli tactic signals are processed by a single response regulator, CheY, and a phosphatase, CheZ, signal processing in S. meliloti involves a retrophosphorylation loop with two response regulators, CheY1 and CheY2, but no phosphatase (49,53,54). In addition, a new periplasmic motor protein, MotC, controls flagellar rotary speed in an as yet enigmatic way (41). The arrangement of chemotaxis (che), flagellar (fla, flg, flh, and fli), motility (mot), and regulatory (visN and visR) genes differs from the enterobacterial pattern in that all 51 known genes are clustered in one contiguous 56-kb chromosomal region, the flagellar regulon (19,55). Two genes, visN and visR (assigned class IA), encode the LuxR-type subunits of a heterodimeric (or heterotetrameric) global transcriptional activator, VisNR (52). Inactivating deletions of visN or visR were shown to result in the loss of class II (flg, flh, fli, and mot) and class III (fla and che) gene expression, suggesting that their transcription is directly controlled by the global regulator VisNR (52). However, while VisNR is synthesized throughout growth, swimming motility is restricted to exponential growth. We describe here another master regulator, Rem (regulator of exponential growth motility) (Smc03046 [19]), that actively controls the transcription of class II genes and that confines their expression to the exponential phase of bacterial growth. The monocistroni...
Abnormal hyperphosphorylation of tau is believed to constitute a critical biochemical event in the process of neurofibrillary degeneration of Alzheimer's disease. We have developed a cellular model where apparently authentic PHF-like tau hyperphosphorylation is induced by okadaic acid. To gain deeper insight into the complex mechanisms of this pathological process we tested a variety of kinase inhibitors in this model. We found that K252a is differentiated from staurosporine by its inhibition of ERK2: both compounds are structurally related microbial metabolites generally believed to have only moderate kinase selectivity. However, since ERK2 inhibitors are exceedingly rare, we used this differential inhibitory property of K252a to demonstrate the involvement of ERK2 in PHF-type tau hyperphosphorylation. K252a was uniquely able to completely suppress the okadaic acid-induced tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by way of including ERK2 in its inhibitory spectrum, and to conserve the normal binding of tau to tubulin. GSK3 inhibitors partially affected the normal state of tau phosphorylation in SH-SY5Y cells, but had no impact on okadaic acid-induced tau hyperhosphorylation. As K252a is the first molecule identified capable of preventing the spectrum of PHF-like tau hyperphosphorylation markers, it may represent a conceptual starting point for therapeutic development of suitable spectrum kinase inhibitors.
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