Calpain Induces N-terminal Truncation of β-Catenin in Normal Murine Liver Development

Lade, Abigale; Ranganathan, Sarangarajan; Luo, Jianhua; Monga, Satdarshan P.

doi:10.1074/jbc.m112.378224

Cited by 34 publications

(35 citation statements)

References 67 publications

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“…72,73 However, calpain-mediated N-terminal truncation of β-catenin may enhance T-cell factor-dependent transcription by increasing accumulation of active 75-kDa β-catenin protein in some tissues or cancers. 74,75 The different roles of calpain in different tissues could be because of multiple cleavage sites in β-catenin 36,76 or different molecular complexes formed by β-catenin in different tissues. In ASCs, we observed the accumulation of smaller degradation fragments of β-catenin.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Shen

Zuo

Wang

et al. 2016

Circulation Research

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Rationale: Autologous adipose-derived stromal cells (ASCs) offer great promise as angiogenic cell therapy for ischemic diseases. Because of their limited self-renewal capacity and pluripotentiality, the therapeutic efficacy of ASCs is still relatively low. Thromboxane has been shown to play an important role in the maintenance of vascular homeostasis. However, little is known about the effects of thromboxane on ASC-mediated angiogenesis. Objective: To explore the role of the thromboxane-prostanoid receptor (TP) in mediating the angiogenic capacity of ASCs in vivo. Methods and Results: ASCs were prepared from mouse epididymal fat pads and induced to differentiate into endothelial cells (ECs) by vascular endothelial growth factor. Cyclooxygenase-2 expression, thromboxane production, and TP expression were upregulated in ASCs on vascular endothelial growth factor treatment. Genetic deletion or pharmacological inhibition of TP in mouse or human ASCs accelerated EC differentiation and increased tube formation in vitro, enhanced angiogenesis in in vivo Matrigel plugs and ischemic mouse hindlimbs. TP deficiency resulted in a significant cellular accumulation of β-catenin by suppression of calpain-mediated degradation in ASCs. Knockdown of β-catenin completely abrogated the enhanced EC differentiation of TP-deficient ASCs, whereas inhibition of calpain reversed the suppressed angiogenic capacity of TP re-expressed ASCs. Moreover, TP was coupled with Gαq to induce calpain-mediated suppression of β-catenin signaling through calcium influx in ASCs. Conclusion: Thromboxane restrained EC differentiation of ASCs through TP-mediated repression of the calpain-dependent β-catenin signaling pathway. These results indicate that TP inhibition could be a promising strategy for therapy utilizing ASCs in the treatment of ischemic diseases.

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Section: Discussionmentioning

confidence: 99%

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Shen

Zuo

Wang

et al. 2016

Circulation Research

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“…We have identified the presence of a truncated form of β-catenin (75 kDa) in addition to the full-length form (97 kDa) at specific hepatic developmental stages (44). The truncated form at low levels is initially evident at around embryonic day 12.5 but becomes the predominant species from E16.5 to the perinatal stage, following which the full length again becomes the dominant species.…”

Section: Wnt Signaling In Hepatic Development: Temporal Role and Regumentioning

confidence: 99%

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Monga

2014

gene expr

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Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle is regulated by β-catenin-TCF complex. Thus β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process, will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

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“…In liver, β-catenin signaling cascade is mostly quiescent in hepatocytes except in the Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein shows constitutive β-catenin activation [33]. Our data suggests that ghrelin facilitates GSK-3β phosphorylation which leads to nuclear translocation of β-catenin.…”

Section: Fig8mentioning

confidence: 78%

Ghrelin Stimulates Hepatocyte Proliferation via Regulating Cell Cycle Through GSK3β/Β-Catenin Signaling Pathway

Wang

Zheng

Yin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Obesity is associated with a reduction in ghrelin, a 28 aa gastric hormone. Whether reduced ghrelin contributes to the impaired proliferation of hepatocytes associated with obesity-related steatosis remains largely unknown. Here we examined the effects of ghrelin on the proliferation of hepatocytes derived from lean and obese mice. Methods: AML 12 cells or hepatocytes isolated from mice fed normal chow diet (NCD) or high fat diet (HFD) were used. Effects of ghrelin on hepatocyte proliferation were detected with CCK8 assay and EdU staining. Cell cycle was analyzed by flow cytometry. Levels of proliferation markers was examined by Western blot. Results: Growth hormone secretagogue receptor 1a (GHS-R1a) mRNA and protein were present in hepatocytes. Levels of GHS-R1a were increased upon ghrelin treatment. Ghrelin significantly increased hepatocyte proliferation measured by Cell Counting Kit-8(CCK8) assay and EdU staining in a dose- and time-dependent manner. Proportion of cells in S phase was markedly increased upon treatment with ghrelin. Ghrelin significantly increased levels of proliferating cell nuclear antigen (PCNA) and cyclin D1, while reducing p27 in hepatocytes from mice fed NCD or HFD. Deletion of GHS-R1a completely abolished the effects of ghrelin in cultured hepatocytes. Ghrelin stimulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3β), leading to subsequent increase of nuclear β-catenin in hepatocytes derived from lean and obese mice. This effect was dependent on the GHS-R1a. Conclusion: Ghrelin activates GHS-R1a to stimulate hepatocyte proliferation via GSK3/β-catenin signaling pathway.

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Calpain Induces N-terminal Truncation of β-Catenin in Normal Murine Liver Development

Cited by 34 publications

References 67 publications

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Ghrelin Stimulates Hepatocyte Proliferation via Regulating Cell Cycle Through GSK3β/Β-Catenin Signaling Pathway

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