CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38(MAPK), a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21(CIP1/WAF1). These findings establish a function for CD44v in regulation of ROS defense and tumor growth.

Takamura et al. show that most lung CD8+ TRM cells are not maintained in the inducible bronchus-associated lymphoid tissue (iBALT) but are maintained in specific niches created at the site of tissue regeneration, which are termed as repair-associated memory depots (RAMDs).

Human RECQL1 and RECQL5 belong to the RecQ family that includes Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome causative genes. Cells derived from individuals suffering from these syndromes show significant levels of genomic instability. However, neither RECQL1 nor RECQL5 has been related to a disease, and nothing is known about the functions of RecQL1 and RecQL5. We generated here The Escherichia coli RecQ helicase is one of the proteins involved in the recF recombination pathway that is effective in the recBCD sbcB background (23). In human cells, five genes encoding RecQ helicase homologues have been identified, and three are the causative genes for Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS) (4, 17, 40). The remaining two are RECQL1 and RECQL5 (16,26,27). BS is a rare genetic disorder characterized by retarded growth, sunlight sensitivity, immunodeficiency, male infertility, and predisposition to a wide variety of malignant tumors. The most characteristic feature of BS cells is genomic instability, which is manifested as an elevated frequency of chromosome breaks, interchange between homologous chromosomes, and sister chromatid exchange (SCE) (10). The other two genetic disorders, WS and RTS, also show genomic instability (21).Before we cloned a cDNA encoding RecQL1, we purified this protein and designated it DNA-dependent ATPase Q1 and later DNA helicase Q1 because of its DNA helicase activity (28, 39). Puranam and Blackshear named the gene encoding this protein RECQL (26). Due to these circumstances and the existence of multiple RecQ homologues in higher eukaryotic cells, we propose to designate this gene RECQL1 (5). Although RecQL1 is a major DNA helicase in human cells, the function of this helicase is not known at all (28).The fourth and fifth RECQ homologues, originally called RecQ4 and RecQ5 and recently called RECQL4 and RECQL5 (5, 17), were cloned in 1998 after a search for sequences similar to the RecQ helicase motifs in the expressed sequence tag database (16). Mutations in the RECQL4 gene have been found in patients with RTS, a rare genetic disorder characterized by premature aging and a predisposition to cancers such as those typical of WS (17). At present, no genetic disorder has been identified that is caused by mutations in the RECQL1 or RECQL5 gene. This circumstance suggests that RecQL1 and RecQL5 are indispensable for cell viability.In contrast to human cells, a unicellular eukaryote, Saccharomyces cerevisiae, has a sole gene that encodes a RecQ helicase homologue, SGS1 (slow growth suppressor 1). The sgs1 mutants show multiple phenotypes, such as sensitivity to methyl methanesulfonate (MMS) and hydroxyurea, chromosome missegregation, poor sporulation, premature aging, and checkpoint defects (6,8,22,30,36,37). In addition, sgs1 mutants show phenotypes of mitotic hyper-recombination, including interchromosomal homologous recombination, intrachromosomal excision recombination, illegitimate recombination, and unequal sister chromatid recombin...

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The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. For the precise analysis of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, these subsets must be transferred into recipients that are completely free of T cells and pathological changes. We used athymic NOD nude mice, which congenitally lack mature T cells and are free of insulitis and hyperglycemia up to the age of 60 weeks, as recipients for this purpose. To the nude recipients we transferred either one of a highly purified CD4+ or CD8+ T cell subset derived from non-diabetic female NOD mice; any in vivo increase in the contaminating T cell subsets was prevented by injecting the antibody homologous to it. Most of the T cell-reconstituted recipients were treated with cyclophosphamide to promote the onset of overt diabetes. Transfer of the CD8+ T cell subset alone did not induce insulitis or hyperglycemia. In contrast, transfer of the CD4+ T cell subset alone produced insulitis, but not hyperglycemia, in all the recipients. However, the subsequent transfer of CD8+ T cells into CD4+ T cell-reconstituted recipients induced severe insulitis and hyperglycemia in almost all the recipients. In these diabetic recipients, we observed severe damage of the pancreatic islets and the infiltration of a large number of CD8+ T cells into the remaining islets; insulin-secreting beta cells were no longer detected. These results suggest that CD4+ T cells play a predominant role in the development of insulitis and that CD8+ T cells migrate into the islets and are subsequently, with the aid of CD4+ T cells, differentiated into killer cells which act against beta cells.

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OBJECTIVE -Postprandial hyperglycemia has emerged as a new glycometabolic condition associated with an excessive risk for coronary artery disease. We therefore attempted to evaluate the frequency of postchallenge hyperglycemia in patients with acute coronary syndrome (ACS) who were not previously diagnosed to have diabetes and did not have a fasting glucose concentration of Ն7 mmol/l or an HbA 1c level Ͼ6.0%. We further correlated the presence of postchallenge hyperglycemia with the extent of coronary atherosclerosis. RESEARCH DESIGN AND METHODS-In all, 134 consecutive ACS patients who met the above inclusion criteria were studied. An oral glucose tolerance test was performed before discharge.RESULTS -The mean age, fasting glucose, and HbA 1c were 60 years, 5.15 mmol/l, and 5.4%, respectively. Among ACS patients, impaired glucose tolerance (IGT) and diabetes were found in 50 (37%) and 13 patients (10%), respectively. The homeostasis model assessment for insulin resistance did not differ substantially among the normal glucose tolerance (NGT), IGT, and diabetic groups. Insulinogenic index, however, was lower and the number of stenosed vessels higher in diabetic patients compared with NGT patients.CONCLUSIONS -Postchallenge hyperglycemia, caused primarily by impaired initial insulin secretion, is commonly found in Japanese ACS patients who have not been previously diagnosed with diabetes, and this phenomenon is considered to be associated with advanced coronary atherosclerosis. Therefore, the present study strongly supports the notion that oral glucose tolerance test assessment of postchallenge hyperglycemia is essential to identify any previously undiagnosed diabetes cases among Japanese ACS patients. Diabetes Care 28:1182-1186, 2005T he number of diabetic patients in Japan is now estimated to be Ͼ6.8 million (1). Furthermore, the number of diabetic patients in Japan and other southeastern Asian countries is expected to increase at the fastest rate worldwide. This trend, together with its associated complications that involve a substantial utilization of resources, make diabetes an extremely important health problem in Japan.Impaired insulin secretion or/and impaired insulin sensitivity play a pivotal role in the development of type 2 diabetes. Possible contributions of these two factors have been shown to be ethnicity dependent to some extent (2,3). In the Caucasian population, a decreased insulin sensitivity is a primary metabolic defect underlying glucose intolerance, whereas an impaired insulin secretion mainly accounts for glucose intolerance in the Japanese population, among other Asian populations (4,5). As a consequence, Caucasian diabetic patients are often accompanied by obesity and increased fasting glucose concentrations, whereas Japanese counterparts are relatively lean and having normal fasting glucose levels but increased postprandial hyperglycemia.An increased prevalence of glucose intolerance has been previously reported in patients with acute coronary syndrome (ACS) in a European population (6). ...

Cell‐surface molecules containing growth factor receptors, adhesion molecules and transporter proteins are often over‐expressed in various cancer cells, and could be regarded as suitable targets for therapeutic monoclonal antibodies (mAb). Anti‐cancer therapeutic mAb are claimed to bind these cell‐surface molecules on viable cancer cells: therefore, it is necessary to produce mAb recognizing epitopes on the extracellular domains of native but not denatured proteins. We have experienced difficulty in obtaining mAb bound to viable cancer cells using synthetic peptides or recombinant proteins produced in bacteria as immunogens, although these immunogens are relatively easy to prepare. In this context, we have concluded that viable cancer cells or cells transfected with cDNA encoding target proteins are suitable immunogens for the production of anti‐cancer therapeutic mAb. Furthermore, we selected rats as the immunized animals, because of their excellent capacity to generate diverse antibodies. Because many target candidates are multi‐pass (type IV) membrane proteins, such as 7‐pass G protein‐coupled receptors and 12‐pass transporter proteins belonging to the solute carrier family, and their possible immunogenic extracellular regions are very small, production of specific mAb was extremely difficult. In this review, we summarize the successful preparation and characterization of rat mAb immunized against the extracellular domain of type I, type II and type IV membrane oncoproteins fused to green fluorescent protein as an approach using reverse genetics, and also introduce the discovery of cell‐death‐inducing antibodies as an approach using forward genetics and a strategy to produce reshaped antibodies using mimotope peptides as the immunogen. (Cancer Sci 2011; 102: 25–35)