Ca &lt;sup&gt;2+&lt;/sup&gt; Signaling in Epithelial Restitution

Rao, Jialing; Wang, J.-Y.

doi:10.1159/000060957

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…Mucosal restitution is an important and primary repair modality in the GI tract, and its dysregulation underlies various critical pathological states such as mucosal bleeding and ulcers, disruption of epithelial integrity, and barrier dysfunction [8,43,44]. Epithelial restitution occurs as a consequence of IEC migration to reseal superficial wounds, a process independent of cell proliferation [13,45-48]. In contrast, chronic healing is the much slower mechanism of replacing lost cells through DNA synthesis and cell division, which takes a much longer time compared with epithelial restitution [42,49].…”

Section: Polyamines and Gut Mucosal Repair: Epithelial Restitution Anmentioning

confidence: 99%

Polyamines and Gut Mucosal Homeostasis

Timmons¹

2013

J Gastrointest Dig Syst

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The epithelium of gastrointestinal (GI) mucosa has the most rapid turnover rate of any tissue in the body and its integrity is preserved through a dynamic balance between cell migration, proliferation, growth arrest and apoptosis. To maintain tissue homeostasis of the GI mucosa, the rates of epithelial cell division and apoptosis must be highly regulated by various extracellular and intracellular factors including cellular polyamines. Natural polyamines spermidine, spermine and their precursor putrescine, are organic cations in eukaryotic cells and are implicated in the control of multiple signaling pathways and distinct cellular functions. Normal intestinal epithelial growth depends on the available supply of polyamines to the dividing cells in the crypts, and polyamines also regulate intestinal epithelial cell (IEC) apoptosis. Although the specific molecular processes controlled by polyamines remains to be fully defined, increasing evidence indicates that polyamines regulate intestinal epithelial integrity by modulating the expression of various growth-related genes. In this review, we will extrapolate the current state of scientific knowledge regarding the roles of polyamines in gut mucosal homeostasis and highlight progress in cellular and molecular mechanisms of polyamines and their potential clinical applications.

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Section: Polyamines and Gut Mucosal Repair: Epithelial Restitution Anmentioning

confidence: 99%

Polyamines and Gut Mucosal Homeostasis

Timmons¹

2013

J Gastrointest Dig Syst

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“…It has been recognized for some time that the control of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions including cell motility, proliferation, and apoptosis (17,18,50). Studies from our laboratory (30,31,33,54) and others (18,21,22) have shown that polyamines are necessary for the stimulation of cell migration after wounding and play a critical role in the maintenance of intestinal mucosal integrity. The process of early mucosal restitution is associated with a dramatic increase in polyamine synthesis both in vivo (17,50,51) and in vitro (30,31,54) after wounding, and depletion of cellular polyamines by inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, with D,L-␣-difluoromethylornithine (DFMO) inhibits cell migration and delays mucosal healing.…”

mentioning

confidence: 99%

Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal epithelial restitution

Rao

Guo

Liu

et al. 2003

American Journal of Physiology-Cell Physiology

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Polyamines are required for the early phase of mucosal restitution that occurs as a consequence of epithelial cell migration. Our previous studies have shown that polyamines increase RhoA activity by elevating cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ]cyt) through controlling voltage-gated K ϩ channel expression and membrane potential (Em) during intestinal epithelial restitution. The current study went further to determine whether increased RhoA following elevated [Ca 2ϩ ]cyt activates Rho-kinase (ROK/ROCK) resulting in myosin light chain (MLC) phosphorylation. Studies were conducted in stable Cdx2-transfected intestinal epithelial cells (IECCdx2L1), which were associated with a highly differentiated phenotype. Reduced [Ca 2ϩ ]cyt, by either polyamine depletion or exposure to the Ca 2ϩ -free medium, decreased RhoA protein expression, which was paralleled by significant decreases in GTP-bound RhoA, ROCK-1, and ROK␣ proteins, Rho-kinase activity, and MLC phosphorylation. The reduction of [Ca 2ϩ ]cyt also inhibited cell migration after wounding. Elevation of [Ca 2ϩ ]cyt induced by the Ca 2ϩ ionophore ionomycin increased GTP-bound RhoA, ROCK-1, and ROK␣ proteins, Rho-kinase activity, and MLC phosphorylation. Inhibition of RhoA function by a dominant negative mutant RhoA decreased the Rho-kinase activity and resulted in cytoskeletal reorganization. Inhibition of ROK/ROCK activity by the specific inhibitor Y-27632 not only decreased MLC phosphorylation but also suppressed cell migration. These results indicate that increase in GTP-bound RhoA by polyamines via [Ca 2ϩ ]cyt can interact with and activate Rho-kinase during intestinal epithelial restitution. Activation of Rho-kinase results in increased MLC phosphorylation, leading to the stimulation of myosin stress fiber formation and cell migration. mucosal injury; intracellular calcium; Cdx2 gene; dominant negative mutant RhoA; cytoskeleton THE SMALL GTPase Rho functions as a molecular switch of various cellular processes by shuttling between the inactive GDP-bound form and the active GTP-bound form (11,14). Rho exerts its distinct actions through interactions with specific targets. Recently, numerous effector molecules of Rho have been identified, including protein kinase N (PKN) (3, 55), ROK/ROCK (20, 40), the myosin-binding subunit of myosin phosphatase (15), p140mDia (56), citron and citron-kinase (19), rhophilin (55), rhotekin (35), and rectifier potassium channel (4). Among these effectors, ROK/ROCK is characterized as a downstream target of Rho and has been implicated in the regulation of cell shape and dynamic reorganization of cytoskeletal proteins (1,13,25,37,44,47). ROK/ROCK is commonly divided into two isoforms, ROCK-I and ROCK-II, corresponding to ROK␤ and ROK␣, respectively. The active form of Rho interacts with the COOH-terminal portion of the putative coiled-coil domain of ROK/ROCK and activates its phosphotransferase activity (20). Increasing evidence indicates that activated ROK/ROCK regulates the phosphorylation of myosin light chain (...

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“…The next step is migration of the cells (fi g. 1) in order to cover the denuded basal lamina (e. g., in the gastric mucosa cells migrate approximately 1-2 µm/min [44]). This is supported by various regulatory peptides ('motogens') [41], cytosolic Ca 2+ [49] and polyamines [50]. Cell migration is also dependent upon extracellular matrix (ECM) proteins [27]), and migratory cells in the wounded area change their expression pattern, e. g. concerning fi bronectin, integrins and metalloproteases [33,51].…”

mentioning

confidence: 99%

Trefoil factors

Hoffmann

2005

Cell. Mol. Life Sci.

184

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Rapid repair of mucous epithelia is essential for preventing inflammation which is a critical component of cancer progression. 'Restitution' is an early repair process which can begin within minutes and is achieved via the migration of neighbouring cells into the wounded area. Mucosal restitution is a multistep process which requires continuous blood flow and includes at least (i) the reduction of cell-cell contacts and a shift in the cell shape towards a migratory phenotype (characteristics of the epithelial-mesenchymal transition), (ii) migration of cells, (iii) repolarization and formation of tight junctions (morphological restitution) and (iv) restoration of barrier function (transmucosal epithelial resistance, functional restitution). Secretory TFF (trefoil factor family) peptides TFF1, TFF2 and TFF3 are well known for their potent protective and healing effects after mucosal damage (function as 'luminal surveillance peptides'). Here, the contributions of the TFFs during the different steps of mucosal restitution are discussed, i. e. the modulation of cell-cell contacts, their motogenic activity and synergy with epidermal growth factor, their anti-apoptotic and pro-angiogenic effects. Special emphasis has been given to discussion of the various signal transduction networks triggered by TFFs. It is becoming increasingly clear that these pathways differ depending on the respective TFF.

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Ca <sup>2+</sup> Signaling in Epithelial Restitution

Cited by 10 publications

References 46 publications

Polyamines and Gut Mucosal Homeostasis

Polyamines and Gut Mucosal Homeostasis

Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal epithelial restitution

Trefoil factors

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