Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

Zhong, Bihui; Strnad, Pavel; Toivola, Diana M.; Guo, Tao; Ji, Xuhuai; Greenberg, Harry B.; Omary, M. Bishr

doi:10.1091/mbc.e07-02-0180

Cited by 23 publications

(26 citation statements)

References 71 publications

(88 reference statements)

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“…The first Reg gene was isolated from a regenerating islet-derived cDNA library in rats (15). Reg family proteins act on β cells and other cells as autocrine or paracrine growth factors (16,(28)(29)(30)(31)(32)(33). In mice, RegI and RegII proteins expressed in regenerating islets and pancreatic exocrine tissues (15,34,35).…”

Section: Discussionmentioning

confidence: 99%

Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Gong

Liu

Wang

et al. 2012

Mol Med

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Basal and adaptive β-cell regeneration capacity declines with old age, but the underlying molecular mechanisms remain incompletely understood. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) is considered a multifunctional enzyme and transcription factor that regulates pancreatic β-cell death, regeneration and insulin secretion. We analyzed the capacity of β-cell regeneration in 2-month-old (young) and 12-month-old (old) wild-type (WT) and PARP-1 -/-mice before and after low-dose streptozotocin (STZ), a stimulus of β-cell regeneration and the underlying mechanism. Before STZ administration, young WT and PARP-1 -/-mice showed similar β-cell proliferation. By contrast, old WT but not old PARP-1 -/-mice showed severely restricted β-cell proliferation. In further assessment of the adaptive β-cell regeneration capacity with age, we observed that with a single low dose of STZ, young WT and PARP-1 -/-mice showed a similar increase in β-cell proliferation, with few changes in old WT mice.Surprisingly, adaptive β-cell proliferation capacity was significantly higher in old PARP-1 -/-mice than old WT mice after STZ administration. The ability of β-cell mass to expand was associated with increased levels of the regenerating (Reg) genes RegI and RegII but not RegIV. Therefore, PARP-1 is a key regulator in β-cell regeneration with advancing age in mice.

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Section: Discussionmentioning

confidence: 99%

Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Gong

Liu

Wang

et al. 2012

Mol Med

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“…1,6,8 Microarray analysis of K8-null and WT pancreata show, however, that multiple genes are differentially regulated, such as the regenerating islet-derived protein II (Reg-II) which is dramatically upregulated in the pancreas of K8-null mice and in transgenic mice harboring human keratin mutations. 9 In addition, mouse pancreata cope well with modest levels of K8/K18 overexpression, while high expression is toxic to the pancreas and leads to atrophy and increased keratin phosphorylation at older age, while keratin overexpression in the liver is tolerated well. [10][11] Together these studies suggest that keratins in the liver and pancreas have different functions.…”

Section: Toivola Et Al Dovepressmentioning

confidence: 99%

“…34,35 Virus-dependent roles for keratinspossible mechanisms of action One potential compensatory mechanism that may account for pancreas-specific functional redundancy for keratin absence is the marked up-regulation of Reg-II in K8-null pancreata. 9 Reg-II is a stress-inducible protein that is normally upregulated 1-4 days after caerulein and CDD-induced pancreatitis and is likely involved in the amelioration Keratins in coxsackievirus-induce pancreatitis Dovepress submit your manuscript | www.dovepress.com Dovepress of pancreatitis. 36,9 Therefore, Reg-II upregulation under basal conditions in K8-null, K18-null, and K18 R90C pancreata is a potential pro-survival candidate for the observed recovery of K8-null mice after CVB4-P infection.…”

Section: Cell Health and Cytoskeletonmentioning

confidence: 99%

“…9 Reg-II is a stress-inducible protein that is normally upregulated 1-4 days after caerulein and CDD-induced pancreatitis and is likely involved in the amelioration Keratins in coxsackievirus-induce pancreatitis Dovepress submit your manuscript | www.dovepress.com Dovepress of pancreatitis. 36,9 Therefore, Reg-II upregulation under basal conditions in K8-null, K18-null, and K18 R90C pancreata is a potential pro-survival candidate for the observed recovery of K8-null mice after CVB4-P infection. Reg-II is also one of the major proteins increased during the recovery period after CVB4-P infection in normal mice, 14 but not during CVB4-V infection which could explain the lack of protection or recovery from CVB4-V infection.…”

Section: Cell Health and Cytoskeletonmentioning

confidence: 99%

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Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Toivola¹,

Ostrowski²,

Baribault³

et al. 2009

CHC

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Keratins 8 and 18 (K8/K18) are the two major intermediate filament proteins in hepatocytes and pancreatic acinar cells. Acinar cell keratins are organized as cytoplasmic and apicolateral filaments. An important role of hepatocyte K8/K18 is to maintain cellular integrity, while this cytoprotective function of K8/K18 is not evident in the pancreas since keratin-deficient mice cope well with pancreatitis models. To further study the roles of keratins in the exocrine pancreas, we used coxsackievirus B4-models, CVB4-V and CVB4-P, to induce severe acute/chronic pancreatitis and acute pancreatitis, respectively, in K8-null (which lack acinar keratins) and K18-null (which lack cytoplasmic keratins) mice. Despite similar virus titers in all mice, CVB4-V resulted in 40% mortality of the K8-null mice 14 days post-infection compared to no lethality of WT and K18-null mice. In contrast, K8-null mice were far less susceptible to CVB4-P-induced damage as determined by histology and serology analysis, and they recover faster than WT and K18-null mice. After CVB4 virus infection, keratins aggregated during acinar degranulation, and K8/K18 site-specific phosphorylation was observed during degranulation and recovery. Hence, keratins significantly affect CVB4 virulence, positively or negatively, depending on the virus subtype and keratin makeup, in a virus replication-independent manner.

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“…Moreover, the Reg2 level was markedly upregulated in the pancreas of keratin 8 knockout mice and during the injury and recovery phases of two different models of pancreatitis in wild-type mice. Reg2 was thus proposed to be a cytoprotective protein, the expression of which is regulated by keratin filament organization and phosphorylation (33). We propose that, in pancreatic cells, Reg2 plays a protective role against the development of diabetes and acute pancreatitis.…”

mentioning

confidence: 91%

Pancreatic Acinar-Specific Overexpression of Reg2 Gene Offered No Protection Against Either Experimental Diabetes or Pancreatitis in Mice.

Li¹,

Wang²

2010

The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego

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Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3␦] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet ␤-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3␣ increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased ␤-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 promoter (Ela-Reg2) to develop an acinar cell-specific overexpression of the Reg2 gene. Western blot analysis, real-time PCR, and immunohistochemistry revealed barely detectable levels of endogenous Reg2 in the pancreas of normal wild-type mice and increased Reg2 levels in the pancreas of Ela-Reg2 mice that were similar to or higher than Reg2 levels induced in experimental diabetes or pancreatitis. Compared with wild-type littermates, growth, blood glucose and insulin levels, and glucose tolerance were normal in Ela-Reg2 mice; pancreatic histology revealed no change in endocrine or exocrine tissues. Acinar-specific overexpression of the Reg2 gene offered no protection against streptozotocin-induced ␤-cell damage and diabetes, in hyperglycemia and weight loss, and no advantage in restoring glucose homeostasis and islet function within 3 mo. Furthermore, serum amylase level and pancreatic histochemistry showed that Reg2 overexpression did not protect acinar cells against caerulein-induced acute pancreatitis. In contrast to INGAP or Reg3␤, exocrine overexpression of Reg2 offered no protection to the endocrine or exocrine pancreas, indicating clear subtype specificities of the Reg family of proteins.caerulein; immunohistochemistry; pancreatic islets; streptozotocin; transgenic mice REG PROTEINS CONSTITUTE a conserved family of seven members (Reg1, Reg2, Reg3␣, Reg3␤, Reg3␦, Reg3␥, and Reg4) in rodents; their production in the pancreas (including the islets of Langerhans) was induced upon endocrine ␤-cell or exocrine acinar cell damage (2,11,14,15). While some of these proteins [Reg1 and islet neogenesis-associated protein (INGAP or Reg3␦)] have been implicated in promoting ␤-cell replication and/or neogenesis in in vivo studies in transgenic and knockout mice (24 -26, 32), the roles of the other five proteins have not been well characterized. A unique seven-amino acid insertion (QVAEEDE) near its NH 2 terminus distinguishes Reg2 (found only in mice and hamsters) from other Reg proteins (4, 29). Results from a recent dual-labeled immunohi...

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Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

Cited by 23 publications

References 71 publications

Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Pancreatic Acinar-Specific Overexpression of Reg2 Gene Offered No Protection Against Either Experimental Diabetes or Pancreatitis in Mice.

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