In Escherichia coli, the transcription factor sigma s, encoded by rpoS, controls the expression of a large number of genes involved in cellular responses to a diverse number of stresses, including starvation, osmotic stress, acid shock, cold shock, heat shock, oxidative DNA damage, and transition to stationary phase. A list of over 50 genes under the control of rpoS has been compiled. The transcription factor sigma s acts predominantly as a positive effector, but it does have a negative effect on some genes. The synthesis and accumulation of sigma s are controlled by mechanisms affecting transcription, translation, proteolysis, and the formation of the holoenzyme complex. Transcriptional control of rpoS involves guanosine 3',5'-bispyrophosphate (ppGpp) and polyphosphate as positive regulators and the cAMP receptor protein-cAMP complex (CRP-cAMP) as a negative regulator. Translation of rpoS mRNA is controlled by a cascade of interacting factors, including Hfq, H-NS, dsrA RNA, LeuO, and oxyS RNA that seem to modulate the stability of a region of secondary structure in the ribosome-binding region of the gene's mRNA. The transcription factor sigma s is sensitive to proteolysis by ClpPX in a reaction that is promoted by RssB and inhibited by the chaperone DnaK. Despite the demonstrated involvement of so many factors, arguments have been presented suggesting that sensitivity to proteolysis may be the single most important modulator of sigma s levels. The activity of sigma s may also be modulated by trehalose and glutamate, which activate holoenzyme formation and promote holoenzyme binding to certain promoters.

The standard treatments for chronic lymphocytic leukemia (CLL) include the alkylating agent chlorambucil (CLB) and the nucleoside analog fludarabine (F-ara-AMP, Flu). Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) is a death receptor ligand that induces apoptosis preferentially in tumors. However, CLL cells seem to be resistant to TRAIL-induced apoptosis. The TRAIL apoptotic signaling pathway has also been implicated in genotoxin-induced apoptosis through upregulation of TRAIL death receptors DR4 and DR5. In the present study, we demonstrate that the treatment of primary CLL cells with CLB or Flu increases the mRNA, protein and cell surface expression levels of DR4 and DR5 in a dose-dependent manner. In contrast to CLL cells, drug treatment fails to increase significantly the expression of DR4 or DR5 in normal lymphocytes. CLL cells are, however, resistant to TRAIL-induced apoptosis compared to B-cell lines. In contrast, combinational treatment using CLB or Flu with TRAIL (100 ng/ml) gave a synergistic apoptotic response. Furthermore, TRAIL is readily detectable on the cell surface of CLL cells, but TRAIL expression fails to increase following drug treatment. Preventing TRAIL from interacting with DR4 and DR5 decreases CLB-induced apoptosis in CLL cells. A similar, but less marked effect is observed with Flu. These findings indicate the involvement of the TRAIL apoptotic pathway in the mechanism of action of chemotherapy, and this mechanism could be utilized to sensitize CLL cells to TRAIL-induced apoptosis.

In Escherichia coli, the transcription factor sigma s, encoded by rpoS, controls the expression of a large number of genes involved in cellular responses to a diverse number of stresses, including starvation, osmotic stress, acid shock, cold shock, heat shock, oxidative DNA damage, and transition to stationary phase. A list of over 50 genes under the control of rpoS has been compiled. The transcription factor sigma s acts predominantly as a positive effector, but it does have a negative effect on some genes. The synthesis and accumulation of sigma s are controlled by mechanisms affecting transcription, translation, proteolysis, and the formation of the holoenzyme complex. Transcriptional control of rpoS involves guanosine 3',5'-bispyrophosphate (ppGpp) and polyphosphate as positive regulators and the cAMP receptor protein-cAMP complex (CRP-cAMP) as a negative regulator. Translation of rpoS mRNA is controlled by a cascade of interacting factors, including Hfq, H-NS, dsrA RNA, LeuO, and oxyS RNA that seem to modulate the stability of a region of secondary structure in the ribosome-binding region of the gene's mRNA. The transcription factor sigma s is sensitive to proteolysis by ClpPX in a reaction that is promoted by RssB and inhibited by the chaperone DnaK. Despite the demonstrated involvement of so many factors, arguments have been presented suggesting that sensitivity to proteolysis may be the single most important modulator of sigma s levels. The activity of sigma s may also be modulated by trehalose and glutamate, which activate holoenzyme formation and promote holoenzyme binding to certain promoters.