The soxRS regulon protects Escherichia coli from superoxide and nitric oxide stress. SoxR protein, a transcription factor that senses oxidative stress via its [2Fe-2S] centers, transduces the signal to the soxS promoter to stimulate RNA polymerase. Here we describe 29 mutant alleles of soxR that cause defects in the activation of soxS transcription in response to paraquat, a superoxide stress agent. Owing to the selection and screen used in their isolation, most of these mutant alleles encode proteins that retained specific binding activity for the soxS promoter in vivo. The mutations were found throughout the SoxR polypeptide, although those closer to the N terminus typically exhibited greater defects in DNA binding. The degree of the defect in the transcriptional response to superoxide caused by each mutation was closely paralleled by its impaired response to nitric oxide. This work begins the general identification of the residues in the SoxR polypeptide that are critical for transducing oxidative stress signals into gene activation.Reactive oxygen species (ROS) are generated as a consequence of the incomplete reduction of oxygen and are unavoidable by-products of aerobic metabolism. If not disposed of efficiently, ROS can cause cellular and genetic damage leading to carcinogenesis, senescence, and neurodegenerative disorders (12, 13). Because cells under oxidative stress are at risk for lethal or mutagenic damage, all aerobic organisms have evolved defense mechanisms to cope with ROS. Part of this response involves the reprogramming of gene expression to increase levels of antioxidant enzymes such as superoxide dismutase and catalase, which limit the levels of superoxide (O 2˙Ϫ ) and hydrogen peroxide, respectively.The study of oxidative stress responses in bacteria has increased our understanding of the biochemical mechanisms whereby ROS levels are sensed by the cell and transduced into changes in gene expression (36,43). The soxRS regulon of Escherichia coli mediates a response that protects the cell against O 2˙Ϫ , nitric oxide (NO), and redox-cycling agents such as paraquat (PQ). In the presence of these oxidants, SoxR, a transcription factor, is activated and stimulates production of a second transcription factor, SoxS, by up to 100-fold (8). Microarray analyses show that expression of the SoxS protein activates at least 40 genes that encode antioxidant, metabolic, and repair functions (36), although Martin and Rosner (29) estimate that the number of genes under the direct control of SoxS may be fewer.SoxR, a member of the MerR family of transcription factors, is a homodimer of 17-kDa subunits and is constitutively expressed in the cell, albeit in an inactive form. Each monomer of SoxR contains a redox-active [2Fe-2S] center, essential for SoxR's transcriptional activity but not for its ability to bind to the promoter (20,21). SoxR binds the soxS promoter with similar affinities in the apo-and metallo-forms and does not significantly influence RNA polymerase binding (21). Oxidation and reduction of th...

Background: A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM) cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress.

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