Autophagic Cell Death of Pancreatic Acinar Cells in Serine Protease Inhibitor Kazal Type 3—Deficient Mice

Ohmuraya, Masaki; Hirota, Masahiko; Araki, Masatake; Mizushima, Noboru; Matsui, Makoto; Mizumoto, Takao; Haruna, Kyoko; Kume, Shoen; Takeya, Motohiro; Ogawa, Michio

doi:10.1016/j.gastro.2005.05.057

Cited by 140 publications

(71 citation statements)

References 41 publications

(37 reference statements)

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“…1a (top), and was located upstream the start codon (Ohmuraya et al 2005). Plasmid JTZ-N-lacZ-2272 contains lacZ fused with NLS and with PGK-PAC-PA.…”

Section: Replacement Of Pgk-neo With Lacz Via Cre Mediated Recombinationmentioning

confidence: 99%

“…In addition, SPINK1 has been found to induce the proliferation of a variety of cell lines (Ogawa et al 1985;Niinobu et al 1990). Furthermore, we previously showed that excessive autophagy was induced in the Spink3 knockout mouse, and that Spink3 is essential for maintaining exocrine integrity of the pancreas, possibly acting as a growth factor for the regeneration of acinar cells (Ohmuraya et al 2005(Ohmuraya et al , 2006.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we also used knock-in mice that express the lacZ reporter gene from the Spink3 locus. We previously produced embryonic stem (ES) cells carrying a targeted null allele for Spink3 (Ohmuraya et al 2005). Using these ES cells, we can easily introduce the lacZ reporter gene, via a Cre-mediated recombination system (Araki et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development

Wang

Ohmuraya

Hirota

et al. 2008

Histochem Cell Biol

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Recent evidence shows that the serine protease inhibitor Kazal type 3 (Spink3) has more diverse functions than expected. To gain insight into its function, we analyzed the spatiotemporal expression profile of Spink3, using in situ hybridization (ISH) and a Spink3+/lacZ knock-in mouse, in which lacZ was inserted into the Spink3 locus. Spink3lacZ expression was first observed in the foregut, midgut, hindgut and the forebrain/midbrain junction region at 9.5 days post coitus (dpc). In the pancreas, Spink3 mRNA was detected at 11.5 dpc, before formation of the typical shape of the exocrine structure of the pancreas. Acinar cell expression was clearly identified by 13.5 dpc. After differentiation of the intestinal tract, Spink3lacZ expression was observed in the large intestine at 11.5 dpc, followed by expression in the small intestine at 13.5 dpc, before appearance of intestinal digestive enzymes. Spink3 mRNA and Spink3lacZ activity were also detected in other tissues, including the mesonephric tubules and the urogenital ridge at 11.5 dpc, the genital swelling at 13.5 dpc, the ductus epididymis at 17.5 dpc, and the seminal vesicle at 8 weeks. These data suggest that Spink3 may play important roles in proliferation and/or differentiation of various cell types during development.

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“…1a (top), and was located upstream the start codon (Ohmuraya et al 2005). Plasmid JTZ-N-lacZ-2272 contains lacZ fused with NLS and with PGK-PAC-PA.…”

Section: Replacement Of Pgk-neo With Lacz Via Cre Mediated Recombinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development

Wang

Ohmuraya

Hirota

et al. 2008

Histochem Cell Biol

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“…This profile precisely overlaps with the time frame of decidualization. Serine protease inhibitor Kazal type 3 (SPINK3) is a 6-kDa protein and also called P12 (Chen et al 1998;Ohmuraya et al 2005). In human, the homologous gene designated SPINK1 was originally isolated from the pancreas as an inhibitor of trypsin and other serine proteases (Kazal et al 1948;Turpeinen et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Role of secretory protease inhibitor SPINK3 in mouse uterus during early pregnancy

et al. 2010

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Successful embryo implantation depends on intricate epithelial-stromal cross-talk. However, molecular modulators involved in this cellular communication remain poorly elucidated. Using multiple approaches, we have investigated the spatiotemporal expression and regulation of serine protease inhibitor Kazal type 3 (SPINK3) in mouse uterus during the estrous cycle and early pregnancy. In cycling mice, both SPINK3 mRNA and protein are only expressed during proestrus. In the pregnant mouse, the expression levels of both SPINK3 mRNA and protein increase on days 5-8 and then decline. Spink3 mRNA is expressed exclusively in the uterine glandular epithelium, whereas SPINK3 protein is localized on the surface of both luminal and glandular epithelium and in the decidua. Moreover, SPINK3 in the decidua has been observed in the primary decidual zone on day 6 and the secondary decidual zone on days 7-8; this is tightly associated with the progression of decidualization. SPINK3 has also been found in decidual cells of the artificially decidualized uterine horn but not control horn, whereas Spink3 mRNA localizes in the glands of both horns. The expression of endometrial Spink3 is not regulated by the blastocyst according to its expression pattern during pseudopregnancy and delayed implantation but is induced by progesterone and further augmented by a combination of progesterone and estrogen in ovariectomized mice. Thus, uterine-gland-derived SPINK3, as a new paracrine modulator, might play an important role in embryo implantation through its influence on stromal decidualization in mice.

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“…Malfunctioning lysosomes in pancreatitis allow an imbalance between these two cathepsins, resulting in less cathepsin L and accumulation of active trypsin (Mareninova et al, 2009;Gukovskaya and Gukovsky, 2012). In addition, disruption of endogenous trypsin inhibitors, similar to that seen in cases of CP, can abrogate autophagy (Ohmuraya et al, 2005;Romac et al, 2010). When Spink-3 (the mouse ortholog of SPINK-1) is compromised, autophagy is impaired and acinar cell vacuolization and pancreatic degeneration occurs.…”

Section: Autophagymentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

2015

Frontiers Research Topics

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Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

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Autophagic Cell Death of Pancreatic Acinar Cells in Serine Protease Inhibitor Kazal Type 3—Deficient Mice

Cited by 140 publications

References 41 publications

Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development

Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development

Role of secretory protease inhibitor SPINK3 in mouse uterus during early pregnancy

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

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