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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser-Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor-beta (TGF-beta) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin-like growth factor II (IGF-II), IGF-II receptor (IGF-IIR), IGF-IR, TGF-beta, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF-IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF-beta2 than B10, although the total TGF-beta2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF-beta appears to require binding to the mannose-6-phosphate (M6P) binding site of the IGF-IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF-IIR levels and active TGF-beta2 levels seems to be key. Thus, the strain variation of TGF-beta2/IGF-IIR-mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF-beta levels, 87% of which is TGF-beta2, as well as the levels of active TGF-beta, 64% of which is TGF-beta2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up-regulation of IGF-IIR, which serves to sequester IGF-II from the growth-promoting IGF-IR and to bind more CORT-up-regulated, latent TGF-beta2 for subsequent plasmin-dependent activation; higher levels of TGF-beta2 signaling down-regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions.
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PMID:Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis. 943 20

Growth plate chondrocytes produce proteoglycan-rich type II collagen extracellular matrix (ECM). During cell maturation and hypertrophy, ECM is reorganized via a process regulated by 1alpha,25(OH)(2)D(3) and involving matrix metalloproteinases (MMPs), including MMP-3 and MMP-2. 1alpha,25(OH)(2)D(3) regulates MMP incorporation into matrix vesicles (MVs), where they are stored until released. Like plasma membranes (PM), MVs contain the 1alpha,25(OH)(2)D(3)-binding protein ERp60, phospholipase A(2) (PLA(2)), and caveolin-1, but appear to lack nuclear Vitamin D receptors (VDRs). Chondrocytes produce 1alpha,25(OH)(2)D(3) (10(-8)M), which binds ERp60, activating PLA(2), and resulting lysophospholipids lead to MV membrane disorganization, releasing active MMPs. MV MMP-3 activates TGF-beta1 stored in the ECM as large latent TGF-beta1 complexes, consisting of latent TGF-beta1 binding protein, latency associated peptide, and latent TGF-beta1. Others have shown that MMP-2 specifically activates TGF-beta2. TGF-beta1 regulates 1alpha,25(OH)(2)D(3)-production, providing a mechanism for local control of growth factor activation. 1alpha,25(OH)(2)D(3) activates PKCalpha in the PM via ERp60-signaling through PLA(2), lysophospholipid production, and PLCbeta. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching the MVs in PKCzeta. Direct activation of MMP-3 in MVs requires ERp60. However, when MVs are treated with 1alpha,25(OH)(2)D(3), PKCzeta activity is decreased and PKCalpha is unaffected, suggesting a more complex feedback mechanism, potentially involving MV lipid signaling.
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PMID:1alpha,25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases. 1722 70

As growth plate chondrocytes mature and hypertrophy, they reorganize their proteoglycan-rich type II collagen extracellular matrix (ECM), involving 1,25(OH)(2)D(3)-dependent regulation of matrix metalloproteinases (MMPs). Stromelysin-1 (MMP-3) and 72-kD gelatinase (MMP-2) are found in extracellular matrix vesicles (MVs) and release and activate ECM-bound latent TGF-beta1 and TGF-beta2, respectively. 1,25(OH)(2)D(3) regulates incorporation of MMP-2 and MMP-3 into MVs and release of these enzymes in the ECM. Plasma membranes (PMs) and MVs contain the 1alpha,25(OH)(2)D(3) membrane receptor ERp60 (protein disulfide isomerase A3), phospholipase A(2) (PLA(2)), PLA(2)-activating protein, the nuclear vitamin D receptor and caveolin-1. 1,25(OH)(2)D(3) secreted by chondrocytes binds MV ERp60, activating PLA(2). Resulting lysophospholipids destabilize MV membranes, releasing active MMPs. We examined 1,25(OH)(2)D(3)-dependent activation of latent TGF-beta1 stored in cartilage ECM. Interestingly, TGF-beta1 regulates 1,25(OH)(2)D(3) production. 1alpha,25(OH)(2)D(3) activates PM protein kinase C (PKC)-alpha via ERp60-dependent PLA(2)-signaling, lysophospholipid production and phospholipase C-gamma. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching MVs in PKC-zeta. Direct activation of MV MMP-3 requires ERp60 based on blocking antibodies and PKC based on inhibitor studies. However, treatment of MVs with 1,25(OH)(2)D(3) decreases MV PKC-zeta activity, suggesting more complex feedback mechanisms, potentially involving MV lipid signaling. Our observations indicate that one role of MVs is to provide MMPs at sites distant from the cells. Chondrocytes secrete 1,25(OH)(2)D(3), which acts directly on MV-membranes via ERp60, releasing MMPs. MMP-specific ECM components are hydrolyzed, resulting in release and activation of growth factors that can act back on the cells.
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PMID:1,25-Dihydroxy vitamin D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60-activated matrix vesicle matrix metalloproteinases. 1876 31

Transforming growth factor-betas (TGF-betas) 2 and 3 are expressed in murine embryonic astrocytes in vivo, but their cellular functions are not known. Primary cultures of rat neonatal astroglial cells express mRNA transcripts for TGF-betas 1, 2, and 3, as well as basic fibroblast growth factor (bFGF) and secrete TGF-beta1 and TGF-beta2 protein. TGF-beta3 protein levels cannot be determined at present. While bFGF is mitogenic for these cells, addition of TGF-betas 1, 2, or 3 alone has little effect. However, the effects of bFGF are modulated by TGF-betas in an isoform-specific fashion. Thus, TGF-beta3 and to a lesser extent TGF-beta2, but not TGF-beta1, can reduce the mitogenic effect of bFGF, but TGF-beta1 selectively leads to a change in cell morphology accompanied by colony formation. Basic FGF and TGF-betas alone, but not combinations of bFGF and TGF-betas, increase plasminogen activator (PA) activity of proliferating cultures, while on confluent cultures TGF-betas and bFGF show additive increases in PA activity. While bFGF and TGF-betas alone have little effect on expression of fibronectin, collagen I, or laminin B1 mRNA by these cells, the combination of TGF-betas and bFGF increases expression of collagen I mRNA. The expression of TGF-beta3, but not TGF-beta1 or TGF-beta2, mRNA is increased almost 10-fold by treatment with any TGF-beta isoform. These data show that TGF-betas alone have little effect on astrocyte growth and gene expression, but can alter effects of bFGF in an isoform-dependent manner. Changes in astrocyte proliferation and morphology, as well as expression of collagen and PA, induced by bFGF and TGF-beta1 are discussed in relation to astroglial scarring.
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PMID:Effects of TGF-betas and bFGF on Astroglial Cell Growth and Gene Expression in Vitro. 1991 47