Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein.

Watanabe, Takashi; Yonemura, Yutaka; Yonekura, Hideto; Suzuki, Yuzuru; Miyashita, Hidetoshi; Sugiyama, Kazuo; Moriizumi, Shigeki; Unno, Michiaki; Tanaka, Osamu; Kondo, Hiromichi

doi:10.1073/pnas.91.9.3589

Cited by 240 publications

(193 citation statements)

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“…Reg I is a lectin-related secretary protein originally isolated as an endogenous growth factor in the pancreas (Terazono et al, 1988;Watanabe et al, 1994;Zenilman et al, 1996). In addition to the role of Reg I in the pancreas, we have demonstrated that Reg I functions as a growth factor in gastric cells and is involved in gastric mucosal regeneration (Asahara et al, 1996;Fukui et al, 1998;Kazumori et al, 2000).…”

Section: Introductionmentioning

confidence: 84%

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

et al. 2006

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Reg I (regenerating gene product I) is a growth factor that plays a central role in the generation and regeneration of the gastric mucosal architecture. On the other hand, mouse Reg I mRNA is expressed at the highest levels in the small intestine among the gastrointestinal tissues. In the current study, with the aim to clarify the role of Reg I protein in the small intestine, the temporal and spatial pattern of Reg I expression and the phenotype of Reg I-knockout mice in the tissue were examined. In the wild-type mice, immunohistochemistry localized Reg I protein expression in absorptive cells located in the lower half of the intestinal villi. Reg I expression was undetectable until embryonic day 13 (E13), when the fetal intestine still lacks villous structure; however, it dramatically increased at E17 along with the formation and maturation of the fetal intestinal villi. In the small intestine of the adult Reg I-knockout mice, less densely packed, round-shaped aberrant morphology of the absorptive cells was observed light microscopically, and electron microscopical examination revealed a strikingly loose connection of these cells to the basement membrane. Antiproliferating cell nuclear antigen staining and anti-Ki67 staining demonstrated the marked decrease in the number of proliferating cells in the small intestinal mucosa of the knockout mice. The cell migration speed visualized by one shot labeling of 5-bromodeoxyuridine was significantly slower in the knockout mice. These phenotypes of Reg I-knockout mice emerged, in accordance with the temporal pattern of Reg I expression described above, from E17. Reg I was considered to be a regulator of cell growth that is required to generate and maintain the villous structure of the small intestine.

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Section: Introductionmentioning

confidence: 84%

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

et al. 2006

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“…In gastric cells, the lithostathine protein was shown to be a regulator of gastric mucosal proliferation (Perfetti et al, 1994) and to function as a mitogenic and/or an antiapoptotic factor in the development of early gastric cancer (Sekikawa et al, 2005). Accordingly, Watanabe et al (Watanabe et al, 1994) suggested that Reg1 protein has a trophic effect on isolated islet cells. More recently, a potential role of lithosthatine in normal and neoplastic germ cell proliferation has been also described (Mauro et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

Marchal¹,

Givalois²,

Verdier³

et al. 2012

Neurobiology of Aging

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We analyzed the cellular distribution of the pancreatic inflammatory protein lithostathine and its receptor EXTL3 in the brain of the lemurian primate Microcebus murinus which develops amyloid deposits along with aging. In adult animals (2-4.5 year-old), lithostathine and EXTL3 immunoreactivities were largely distributed in the whole brain, and more intensively in almost all cortical layers and hippocampal formation. Lithostathine was observed in the perikarya and neurites of cortical neurons but also in glial cells in the border of the ventricle and the corpus callosum.In healthy aged animals (8-13 year-old), highest densities of lithostathine containing cells were observed, mainly in occipital and parietal cortex. In aged animals with A deposits, the increase in lithostathine immunoreactivity was lower as compared with aged animals. Noteworthly, lithostathine-immunopositive cells did almost never colocalize with A plaques. In conclusion, lithostathine immunoreactivity in adult Microcebus murinus appeared ubiquitous and particularly in visual, sensorial and cognitive brain areas. Immunoreactivity increased with aging and appeared markedly affect in neuropathological conditions. Its possible neuroprotection or neurodegeneration role in Alzheimer pathology deserves therefore to be investigated.

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“…Modern Pathology ( The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets, 1 and its gene product was shown to have a trophic effect on not only islet but also gastric epithelial cells. 2,3 Recently, many Reg-related genes have been isolated and shown to constitute a multigene family. 4 Among human REG family proteins, REG Ia and REG IV are reportedly overexpressed in a subset of gastric cancer.…”

mentioning

confidence: 99%

“…2,3 Recently, many Reg-related genes have been isolated and shown to constitute a multigene family. 4 Among human REG family proteins, REG Ia and REG IV are reportedly overexpressed in a subset of gastric cancer.…”

mentioning

confidence: 99%

Expression profile of REG family proteins REG Iα and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers

et al. 2009

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Regenerating gene family members 1 (REG Ia) and 4 (REG IV) are overexpressed in a subset of gastric cancers. However, comparative characterization of the expression of these family proteins has remained unclear. Therefore, we aimed to elucidate not only the association between REG protein expression and mucin phenotype but also their significance as a prognostic marker for patients with gastric cancer. The expression of REG Ia, REG IV, CDX2, MUC2, and MUC5AC in gastric cancer tissues was examined by immunohistochemistry. The relationship between REG protein expression and clinicopathological parameters or mucin phenotype was then analyzed. REG Ia and REG IV expression was positive in 33 (52%) and 31 (49%) of 63 gastric cancers examined, respectively. REG Ia expression was significantly related to venous invasion and tumor stage, whereas REG IV expression showed no relationship to clinicopathological features. With regard to mucin phenotype, REG IV expression was significantly correlated with MUC2 and CDX2 expression, suggesting an association with the intestinal mucin phenotype of gastric cancer. On the other hand, REG Ia expression had no correlation with MUC2, CDX2, or MUC5AC in gastric cancer tissues. Expression of REG Ia but not REG IV was an independent predictor of poor outcome in patients with gastric cancer. In addition, patients with gastric cancer negative for both REG Ia and REG IV expression had a significantly better outcome than patients positive for either REG Ia or REG IV. Profiling of REG protein expression is useful to for prognostication of patients with gastric cancer. Modern Pathology ( The regenerating gene (Reg) was originally isolated from regenerating rat pancreatic islets, 1 and its gene product was shown to have a trophic effect on not only islet but also gastric epithelial cells. 2,3 Recently, many Reg-related genes have been isolated and shown to constitute a multigene family. 4 Among human REG family proteins, REG Ia and REG IV are reportedly overexpressed in a subset of gastric cancer. 5-9 Moreover, several microarray analyses have recently isolated REG Ia and REG IV as novel genes that are overexpressed in gastric cancer tissues, 10,11 suggesting that both genes have important functions in gastric carcinogenesis. Indeed, we have previously clarified that REG Ia acts as a trophic and/or anti-apoptotic factor in the development of gastric cancer, 12 and others have reported that REG IV protein confers cell resistance to chemotherapeutic agents, 9 suggesting that these proteins are both associated with tumor progression. It is noteworthy that in non-neoplastic tissues REG Ia and REG IV are commonly expressed not only in endocrine cells but also in metaplastic cells that frequently accompany gastric cancer lesions, 5,8,12,13 implying a possible link between REG protein expression and mucin phenotype of gastric lesions. In addition, there is increasing speculation as to whether REG Ia and REG IV protein expression may

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Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein.

Cited by 240 publications

References 19 publications

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

Expression profile of REG family proteins REG Iα and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers

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