Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serial subculture of primary normal human oral keratinocytes (NHOKs) to the post-mitotic stage induces terminal differentiation, which is in part linked to elevated levels of phospholipase C (PLC)-gamma1. Therefore, PLC-gamma1 may be involved in the signal transduction system that leads to the calcium regulation of subculture-induced keratinocyte differentiation. To test this hypothesis, the expression of PLC-gamma1 in primary NHOKs was blocked by transfecting cells with the antisense PLC-gamma1 cDNA construct. These cells demonstrated dramatic reductions in PLC-gamma1 protein and in the differentiation markers involucrin and transglutaminase following calcium exposure and an increase (15-20%) in in vitro life span versus empty vector-transfected cells. In addition, we established the ability of antisense PLC-gamma1 to block the serial subculture-induced rise in intracellular calcium. Similar observations were made following treatment with the specific PLC inhibitor U73122. These results indicate that the terminal differentiation of NHOKs by serial subculture is associated with PLC-gamma1, which mediates calcium regulation by mobilizing intracellular calcium.
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PMID:Phospholipase C-gamma1 is required for subculture-induced terminal differentiation of normal human oral keratinocytes. 1263 3

Galpha(h), also known as transglutaminase II, has GTPase as well as transglutaminase activities. To better understand the factors affecting these dual enzymatic activities, we examined the optimal pH (at 25 degrees C) and thermal stability (at 37 degrees C) of the activities using membranous Galpha(h) from mouse heart. The optimum pH for the GTPase activity of Galpha(h) is approximately 7.0. As well, the GTP binding activity of Galpha(h) is more thermostable at pH 7.0 than that at pH 9.0. Consistent with these observations on the GTPase function of Galpha(h), both the phospholipase C-delta1 activity and the yield of co-immunoprecipitation of Galpha(h)-coupled phospholipase C-delta1 in alpha(1)-adrenoceptor/Galpha(h)/phospholipase C-delta1 complex preparations were enhanced by incubation with an alpha(1)-agonist, phenylephrine, at pH 7.0. On the other hand, the transglutaminase activity of Galpha(h) is higher in the basic pH range with an optimum activity at pH approximately 9.0. Also, the transglutaminase activity of Galpha(h) is more thermostable at pH 9.0 than that at pH 7.0. These results indicate not only pH as a modulator for the dual functions of Galpha(h), but also provide direct evidence for the involvement of pH in the Galpha(h)-mediated alpha(1)-adrenoceptor signaling system in vitro.
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PMID:Distinct pH modulation for dual function of Galphah (transglutaminase II). 1580 44

We have previously demonstrated that phospholipase C (PLC)-gamma1 is required for calcium-induced human keratinocyte differentiation. In the present study, we investigated whether the activation of PLC-gamma1 by nonreceptor kinases such as src and fyn plays a role in mediating this process. Our results showed that the combination of dominant negative src and fyn blocked calcium-stimulated PLC-gamma1 activity and human keratinocyte differentiation, whereas each separately has little effect. However, unlike the activation of PLC-gamma1 by epidermal growth factor, calcium-induced activation of PLC-gamma1 was not a result of direct tyrosine phosphorylation. Therefore, we examined an alternative mechanism, in particular phosphatidylinositol 3,4,5-triphosphate (PIP3) formed as a product of phosphatidylinositol 3-kinase (PI3K) activity. PIP3 binds to and activates PLC-gamma1. The combination of dominant negative src and fyn blocked calcium-induced tyrosine phosphorylation of the regulatory subunit of PI3K, p85alpha, and the activity of the catalytic subunit of PI3K. PI3K inhibitors blocked calcium activation of PLC-gamma1 as well as the induction of keratinocyte differentiation markers involucrin and transglutaminase. These data indicate that calcium activates PLC-gamma1 via increased PIP3 formation mediated by c-src- and fyn-activated PI3K. This activation is required for calcium-induced human keratinocyte differentiation.
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PMID:Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-gamma1. 1587 86

The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-gamma1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)2D3. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)2D3. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)2D3, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)2D3 action on keratinocytes.
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PMID:Hairless suppresses vitamin D receptor transactivation in human keratinocytes. 1626 53

Tissue TG (transglutaminase) or TG2 is the most ubiquitously expressed member of the large TG family that catalyses deamidation of a glutamine residue, formation of an N epsilon(gamma-glutamyl)-lysine cross-linking between lysine and glutamine residues and/or covalent incorporation of polyamines into a glutamine residue, exerting a number of physiological and/or pathological functions. Extracellular TG2 contributes to wound healing and exacerbation of liver fibrosis through a role in extracellular matrix assembly and cell adhesion. Intracellular TG2 acts as a GTPase in normal cells when the intracellular Ca2+ concentration is as low as 10-20 nM, participating in the transmembrane signalling of phospholipase C delta as a component of alpha1-adrenergic receptor complexes, and thereby supporting the growth of hepatic cells. When cells are injured and the intracellular Ca2+ concentration rises to more than 700-800 nM, TG2 dramatically alters its structure and transforms into a cross-linking enzyme. TG2 primarily exists in the cytosol in normal cells, but is distributed among multiple intracellular milieus during tissue injury or apoptosis. In particular, TG2 has been shown to be abundant in the nuclei of cells undergoing apoptosis, although its role in the nucleus and the underlying mechanisms remain unresolved. Recently, three findings in the study of alcoholic steatohepatitis have shed light on these issues. Omary's group disclosed that TG2-mediated cross-linking of keratin 8 is essential for the formation of Mallory-Denk bodies. We have demonstrated that in both mouse models of alcoholic steatohepatitis and human patients with alcoholic steatohepatitis, TG2 translocates into the nucleus and provokes hepatocyte death via cross-linking and inactivation of a transcription factor, Sp1, leading to down-regulation of the hepatocyte growth factor receptor, c-Met. Furthermore, Giebeler et al. has reported that down-regulation of c-Met is associated with liver fibrosis. In the present review article, we introduce these recent advances in knowledge with regard to the the roles of TG2 in alcoholic steatohepatitis.
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PMID:Recent advances in understanding the roles of transglutaminase 2 in alcoholic steatohepatitis. 2019 18


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