Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response (UPR). Although recent studies have indicated cross-talk between ER stress and oxidative stress, the mechanistic link is not fully understood. By using murine fibrosarcoma L929 cells, in which tumor necrosis factor (TNF) ␣ induces accumulation of reactive oxygen species (ROS) and cell death, we show that TNF␣ induces the UPR in a ROS-dependent fashion. In contrast to TNF␣, oxidative stresses by H 2 O 2 or arsenite only induce eukaroytic initiation factor 2␣ phosphorylation, but not activation of PERK-or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNF␣-induced ROS accumulation and cell death by inhibiting reduction of cellular glutathione levels. Collectively, some, but not all, oxidative stresses induce the UPR, and pre-emptive UPR counteracts TNF␣-induced ROS accumulation.Newly synthesized secretory and membrane-associated proteins are correctly folded and assembled in the endoplasmic reticulum (ER). 2Once ER function is perturbed by various pathological conditions, newly synthesized unfolded proteins accumulate in the ER, resulting in ER stress. To cope with accumulated unfolded ER proteins, mammalian cells trigger a specific response termed the unfolded protein response (UPR) (1-3). There are three distinct signaling pathways that are triggered in response to ER stress, mediated by PERK, ATF6, and IRE1. Under non-pathological conditions, all three components associate with the abundant lumenal chaperon Bip (also known as glucose-regulated protein 78) and this interaction keeps these signaling molecules in an inactive state (4, 5). Once unfolded proteins accumulate in the ER, Bip preferentially associates with the unfolded proteins instead of PERK, ATF6, and IRE1, resulting in activation of their downstream signaling molecules. PERK is an ER-resident serine/threonine protein kinase that phosphorylates the ␣ subunit of eukaryotic translation initiation factor 2 (eIF2␣) (6). Phosphorylation of eIF2␣ subsequently inhibits protein synthesis to prevent further influx of nascent proteins into an already saturated ER lumen. Paradoxically, eIF2␣ phosphorylation induces translation of a transcription factor ATF4 and subsequent expression of the ATF4 target genes, GADD34 and CHOP (7). The second signaling pathway is mediated by the basic leucine zipper-type transcription factor, ATF6. ATF6 is synthesized as a type II transmembrane precursor protein with a molecular mass with 90 kDa (p90 ATF6), and anchored to the ER membrane where it is retained by Bip. In response to ER stress, ATF6 is released from Bip and transported to the Golgi complex (8), where ATF6 undergoes sequential cleavages by two proteases, S1P and S2P (9). The processed form of ATF6 (p50ATF6) translocate...

The activation of NF-jB inhibits apoptosis via a mechanism involving upregulation of various antiapoptotic genes, such as cellular FLICE-inhibitory protein (c-FLIP), Bcl-x L , A1/Bfl-1, and X chromosome-liked inhibitor of apoptosis (XIAP). In contrast, the activation of c-Jun N-terminal kinase (JNK) promotes apoptosis in a manner that is dependent on the cell type and the context of the stimulus. Recent studies have indicated that one of the antiapoptotic functions of NF-jB is to downregulate JNK activation. Further studies have also revealed that NF-jB inhibits JNK activation by suppressing accumulation of reactive oxygen species (ROS). In this review, we will focus on the signaling crosstalk between the NF-jB and JNK cascades via ROS.

IntroductionWork disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.MethodsThe Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.ResultsAt the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.ConclusionsWork disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABLpositive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 lm; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21 CIP1 and p27 KIP1 . These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This structure is disrupted in a variety of human disorders including acute promyelocytic leukemia and viral infections, suggesting that alterations in the nuclear body may have an important role in the pathogenesis of these diseases. In this study, we identified a cDNA encoding a leukocyte-specific nuclear body component designated Sp110. The N-terminal portion of Sp110 was homologous to two previously characterized components of the nuclear body (Sp100 and Sp140). The C-terminal region of Sp110 was homologous to the transcription intermediary factor 1 (TIF1) family of proteins. High levels of Sp110 mRNA were detected in human peripheral blood leukocytes and spleen but not in other tissues. The levels of Sp110 mRNA and protein in the human promyelocytic leukemia cell line NB4 increased following treatment with all-trans retinoic acid (ATRA), and Sp110 localized to PML-Sp100 nuclear bodies in ATRA-treated NB4 cells. Because of the structural similarities between Sp110 and TIF1 proteins, the effect of Sp110 on gene transcription was examined. An Sp110 DNA-binding domain fusion protein activated transcription of a reporter gene in transfected mammalian cells. In addition, Sp110 produced a marked increase in ATRA-mediated expression of a reporter gene containing a retinoic acid response element. Taken together, the results of this study demonstrate that Sp110 is a member of the Sp100/Sp140 family of nuclear body components and that Sp110 may function as a nuclear hormone receptor transcriptional coactivator. The predominant expression of Sp110 in leukocytes and the enhanced expression of Sp110 in NB4 cells treated with ATRA raise the possibility that Sp110 has a role in inducing differentiation of myeloid cells.The nuclear body (also known as nuclear domain 10, promyelocytic leukemia protein [PML] oncogenic domain, and Kr body) is a cellular structure that appears to be involved in the pathogenesis of a variety of human diseases including acute promyelocytic leukemia and acute viral infections. In addition, the nuclear body is a target of antibodies in the serum of patients with the autoimmune disease primary biliary cirrhosis (reviewed in references 17, 31, and 40). By immunohistochemical staining, nuclear bodies appear as 5 to 30 discrete, punctate regions within the nucleus. The number of nuclear bodies in the cell and the intensity of antibody staining of these structures increase in response to heat shock and viral infection, as well as exposure to interferons (IFNs) and heavy metals (3).Although the exact role of the nuclear body in cellular biology is unknown, recent studies suggest that this structure is involved in the regulation of gene transcription. LaMorte and colleagues used an in vivo nucleic acid labeling technique to demonstrate that nascent RNA polymerase II transcripts are present near the nuclear body (23). In addition, Ishov et al. demonstrated that the nuclear body is a preferred site for t...