HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells

Christa, Laurence; Carnot, Françoise; Simón, Marina; Levavasseur, Françoise; Stinnakre, Marie‐Georges; Lasserre, Chantal; Thépot, Dominique; Clément, Bruno; Devinoy, Ève; Bréchot, Christian

doi:10.1152/ajpgi.1996.271.6.g993

Cited by 81 publications

(126 citation statements)

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“…The cloning of HIP/PAP cDNA into an expression vector containing the His-tag has been described elsewhere (24). The recombinant protein contained a 6 Histidine tag at the NH 2 -terminal, followed by the putative signal sequence, the putative propeptide, and the COOH-terminal carbohydrate recognition domain (CRD) of HIP/PAP.…”

Section: Methodsmentioning

confidence: 99%

“…Pancreatic Reg expression in NOD mice was studied with two different affinity-purified rabbit-derived polyclonal anti-Reg primary antibodies. One was produced against a fusion protein of the CRD of HIP/PAP (HIP-CRD) with glutathion-S-transferase (24), and the other was produced against recombinant rat PAP1, the homologue to mouse RegIII␤. Guinea pig anti-insulin antibodies, HRP-labeled anti-guinea pig antibodies, and HRP-labeled anti-rabbit antibodies were purchased (Zymed, Sigma).…”

Section: Purification Of Cd8mentioning

confidence: 99%

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A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice

Gürr

Yavari

et al. 2002

Diabetes

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Genes overexpressed in pancreatic islets of patients with new-onset type 1 diabetes are potential candidates for novel disease-related autoantigens. RT-PCR-based subtractive hybridization was used on islets from a patient who died at the onset of type 1 diabetes, and it identified a type 1 diabetes-related cDNA encoding hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP). This protein belongs to the family of Reg proteins implicated in islet regeneration; its gene contains a putative interleukin-6 (IL-6) response element. Islets from healthy cadaveric human donors released HIP/PAP protein into the culture medium, and this release was enhanced by the addition of IL-6. The expression pattern of mouse homologues of HIP/PAP was determined in pancreata of prediabetic and diabetic NOD mice. Both groups showed positive immunostaining for HIP/PAP in islets and ductal epithelium. To test whether HIP/PAP is a target of isletdirected autoimmunity, we measured splenic T-cell responses against HIP/PAP in NOD mice. Spontaneous proliferation was detected after 4 weeks. Lymphocytes from islet infiltrates and pancreatic lymph nodes from 7-to 10-week-old NOD mice were used to establish an HIP/PAP-specific I-A g7 -restricted T-cell line, termed WY1, that also responded to mouse islets. WY1 cells homed to islets of NOD-SCID mice and adoptively transferred disease when coinjected with purified CD8 ؉ cells from diabetic NOD mice. Our conclusion was that differential cloning of Reg from islets of a type 1 diabetic patient and the response of Reg to the cytokine IL-6 suggests that HIP/PAP becomes overexpressed in human diabetic islets because of the local inflammatory response. HIP/PAP acts as a T-cell autoantigen in NOD mice. Therefore, autoimmunity to HIP/PAP might create a vicious cycle, accelerating the immune process leading to diabetes. Diabetes 51:339 -346, 2002

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Section: Methodsmentioning

confidence: 99%

Section: Purification Of Cd8mentioning

confidence: 99%

A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice

Gürr

Yavari

et al. 2002

Diabetes

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“…20 We discovered the human HIP/PAP gene by differential screening of a hepatocarcinoma 15 and demonstrated that HIP/PAP promoted hepatocyte adhesion in primary cultures and interacted with the proteins of the extracellular matrix. 21 Rat PAPI also promoted the growth of epithelial intestinal cells. 22 In neurons, rat Reg2/HIP/PAPI prevented cell death in primary motor neuron cultures 23 and stimulated mitogenesis in Schwann cells and nerve regeneration.…”

mentioning

confidence: 91%

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

et al. 2006

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Reg2/RegIII␤ is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2؊/؊ mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 g/g), only 50% of the Reg2؊/؊ mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2؊/؊ mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-␣/IL-6 priming signaling by exerting a negative feedback on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-␣/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver. (HEPATOLOGY 2006;44:1452-1464 F as/FasL (APO-1, CD95) interaction is involved in many pathological situations such as graft-versushost disease, liver transplant and major surgical resection, hepatitis B and C, acute alcoholic hepatitis, drug overdose, and some biliary diseases. Fas activation-induced acute liver failure is characterized by massive hepatic necrosis/apoptosis. Survival of patients depends on the speed with which quiescent liver cells re-enter the cell

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“…Regenerating islet-derived (Reg) gene family, initially discovered in connection with islet regeneration after experimental injury to rat pancreas, encodes for a small group of proteins involved in the control of epithelial cell proliferation and differentiation in various organs, including pancreas and intestine. [7][8][9] In humans, the Reg gene family currently consists in four well-established members (Reg1a, Reg1b, Reg3a and Reg4), which are found encoded in tandem on chromosome 2p12, except for Reg4, which is found on 1p12. 10 All Regs are produced in the pancreas and small intestine, whereas Reg4 is only constitutively expressed in colonic epithelium, 11 and their expression is enhanced during inflammatory processes.…”

Section: Introductionmentioning

confidence: 99%

“…14 Higher levels of Reg3a were documented in patients with IBD in comparison to healthy controls, while no significant increase was seen in patients with infectious colitis. 8,17 Reg3a is also increased in the plasma of patients with gastrointestinal GVHD, and this protein has been proposed as a useful biomarker that may improve risk stratification of GVHD patients when combined with clinical stage and histological grading. 19 Our study was performed to evaluate whether serum Reg3a concentration is increased in patients with mucosal enteropathies.…”

mentioning

confidence: 99%

Serum regenerating islet‐derived 3‐alpha is a biomarker of mucosal enteropathies

Marafini

Sabatino

Zorzi

et al. 2014

Aliment Pharmacol Ther

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HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells

Cited by 81 publications

References 0 publications

A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice

A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice

Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

Serum regenerating islet‐derived 3‐alpha is a biomarker of mucosal enteropathies

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