Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High density cDNA microarray screening was used to determine changes in gene expression occurring during the transition between the early luteal (prereceptive) and mid-luteal (receptive) phases in human endometrium. Of approximately 12,000 genes profiled, 693 (5.8%) displayed >2-fold differences in relative levels of expression between these stages. Of these, 370 genes (3.1%) displayed decreases ranging from 2- to >100-fold while 323 genes (2.7%) displayed increases ranging from 2- to >45-fold. Many genes correspond to mRNAs encoding proteins previously shown to change in a similar manner between the proliferative and mid-luteal phases, serving as one validation of the microarray screening results. In addition, novel genes were identified. Genes encoding cell surface receptors, adhesion and extracellular matrix proteins and growth factors accounted for 20% of the changes. Several genes were studied further by Northern blot analyses. These results confirmed that claudin-4/Clostridium perfringens enterotoxin (CPE) receptor and osteopontin (OPN) mRNA increased approximately 4- and 12-fold respectively, while betaig-H3 (BIGH3) decreased >80% during the early to mid-luteal transition. Immunostaining also revealed strong specific staining for claudin-4/CPE, EP(1) and prostaglandin receptor in epithelia, and leukotriene B4 receptor in both epithelia and stroma, at the mid-luteal stage. Collectively, these studies identify multiple new candidate markers that may be used to predict the receptive phase in humans. Some of these gene products, e.g. OPN, may play direct roles in embryo-uterine interactions during the implantation process.
Mol Hum Reprod 2002 Sep
PMID:Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. 1220 Apr 66

Mixed lineage kinase 3 (MLK 3) (also called SPRK or PTK-1) is a recently described member of the family of the mixed lineage kinase subfamily of Ser/Thr protein kinases that interacts with mitogen-activated protein kinase pathways. In order to test the biological relevance and potential interaction of MLK 3 with protein kinase C-mediated signaling pathways, human MLK 3 was stably expressed in rat glomerular mesangial cells using a retroviral vector (LXSN) and the effects of phorbol myristoyl acetate (PMA) on DNA synthesis and osteopontin mRNA expression were examined. In control (vector-transfected) mesangial cells PMA increased [3H]-thymidine incorporation in a concentration-dependent manner. In mesangial cells stably expressing MLK 3, the PMA-induced increase in [3H]-thymidine incorporation was significantly reduced (> 50%). However, the PMA-induced increase in osteopontin mRNA was not affected by MLK 3 expression. To determine the mechanisms of these effects, activation of ERK2, JNK1 and p38 in response to PMA was examined in both vector and MLK 3 transfected cells. ERK2 activation was increased several fold by PMA in control cells but was attenuated significantly in MLK 3 expressing cells, suggesting that MLK 3 expression in mesangial cells can negatively regulate the ERK pathway. PMA had no significant effect on JNK and P38 activation, in either vector- or MLK 3-expressing cells. PD98059, a MEK inhibitor blocked PMA-induced DNA synthesis without affecting osteopontin expression. These results suggest that while protein kinase C activation increases cellular proliferation and osteopontin mRNA expression, over-expression of MLK 3 affects only the PKC-induced DNA synthesis, probably through inhibition of ERK. These results also indicate a novel mechanism of growth regulation by a member of the mixed-lineage kinase family that might have significant therapeutic implications in proliferative glomerulonephritis.
Mol Cell Biochem 2002 Dec
PMID:Mixed lineage kinase 3 inhibits phorbol myristoyl acetate-induced DNA synthesis but not osteopontin expression in rat mesangial cells. 1248 23

Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN-/- osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the alpha(v)beta(3) integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.
Mol Biol Cell 2003 Jan
PMID:Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. 1252 35

The remodeling of chromatin is required for tissue-specific gene activation to permit interactions of transcription factors and coregulators with their cognate elements. Here, we investigate the chromatin-mediated mechanisms by which the bone-specific osteocalcin (OC) gene is transcriptionally activated during cessation of cell growth in ROS 17/2.8 osteosarcoma cells and during normal osteoblast differentiation. Acetylation of histones H3 and H4 at the OC gene promoter was assayed during the proliferative and postproliferative stages of cell growth by using chromatin immunoprecipitation assays with antibodies that recognize different acetylated forms of histones H3 or H4. The results show that the promoter and coding regions of the OC gene contain very low levels of acetylated histones H3 and H4 during the proliferative period of osteoblast differentiation when the OC gene is inactive. Active expression of the OC gene in mature osteoblasts and confluent ROS 17/2.8 cells is functionally linked to preferential acetylation of histone H4 and, to a lesser extent, to acetylation of histone H3. Histone acetylation at the loci for RUNX2 (CBFA1), alkaline phosphatase, bone sialoprotein, osteopontin, and the cell growth regulator p21, which are expressed throughout osteoblast differentiation, is not altered postproliferatively. We conclude that acetylation of histones H3 and H4 is functionally coupled to the chromatin remodeling events that mediate the developmental induction of OC gene transcription in bone cells.
Mol Endocrinol 2003 Apr
PMID:Transcriptional induction of the osteocalcin gene during osteoblast differentiation involves acetylation of histones h3 and h4. 1255 83

The integrin alpha4beta1 fulfills important roles in inflammation and hematopoesis, but its functions in neurons are not well understood. Here we show that the alpha4 subunit is expressed on mouse retinal ganglion cells (RGCs) and undifferentiated retinal neuroblasts during the period of axon extension and migration. To determine if alpha4 integrins expressed by retinal neurons were active, neurons were cultured on known alpha4 ligands in vitro. Recombinant soluble vascular cell adhesion molecule 1 (rsVCAM-1), fibronectin, and osteopontin (OPN) induced neurite outgrowth that was diminished by function blocking antibodies specific for alpha4. Neurite outgrowth on OPN was also blocked by antibodies to the integrin beta1 subunit, implicating the alpha4beta1 heterodimer as one integrin receptor mediating outgrowth on OPN. OPN immunoreactivity was detected in the RGC fiber layer and optic nerve, suggesting that it may act as an alpha4 ligand in vivo. Neurons from chick lumbar sympathetic ganglia, chick dorsal root ganglia, and mouse superior cervical ganglia also extended neurites on rsVCAM-1, suggesting that integrin alpha4beta1 may play a role in the development of multiple neuronal cell types.
Mol Cell Neurosci 2003 Jul
PMID:Integrin alpha4beta1 (VLA-4) expression and activity in retinal and peripheral neurons. 1283 26

Malignant tumors are characterized by excessive growth, immortalization, and metastatic spread, whereas benign tumors do not express gene products that mediate invasion. The molecular basis for this difference is incompletely understood. We have screened signal transduction molecules associated with the epidermal growth factor (EGF) receptor and have identified constitutive phosphorylation, indicative of activation, of Akt kinase in MT2994 breast cancer cells. In contrast, cells of the benign breast epithelial cell lines Comma-D and FSK-7 are immortalized through pathways that are independent of the EGF-phosphatidylinositol 3-kinase-Akt kinase cascade, but this is not associated with invasiveness. Transfection of constitutively active Akt kinase causes accelerated cell division and osteopontin expression. Conversely, dominant-negative Akt kinase slows cell cycle progression and suppresses osteopontin expression. The manipulation of osteopontin expression in this setting by transfection of the gene or its antisense does not affect the growth rate of the cells but alters cell motility and anchorage independence. Therefore, Akt kinase activates two distinct genetic programs: the program of growth and survival, which is independent of osteopontin expression, and the program of invasiveness and anchorage independence, which is mediated by osteopontin. These studies define Akt kinase as a molecular bridge between cell cycle progression and dissemination.
Mol Cell Biol 2003 Sep
PMID:Growth factor signaling induces metastasis genes in transformed cells: molecular connection between Akt kinase and osteopontin in breast cancer. 1294 77

Transplant vasculopathy is a key factor behind the late loss of transplanted organs. Since effective treatment is still lacking, a further understanding of the pathology of this process is important. Here, a rat model of aortic allografts was used and analyzed by immunohistochemistry and biochemical tests. Infrarenal aortic segments were transplanted from F344 to Lewis rats and analysed after 1-12 weeks using isografts as controls. After 1 week, endothelial cells gradually disappeared at the graft lumen as shown by von Willebrand factor staining and cellular activation was detected in the adventitia and intima using cellular retinol-binding protein-1 as a marker. Subsequently, proliferating smooth muscle cells, lymphocytes and macrophages accumulated in the intima as indicated by the appearance of staining for cell- and proliferation-specific antigens (smooth muscle alpha-actin, CD45RC, ED1, cyclin D1 and proliferating cell nuclear antigen). After 4-8 weeks, TUNEL- and Fas-positive cells were observed in the media, denoting progressive apoptosis. In parallel, the developing neointima contained increased immunoreactivity for fibronectin and osteopontin. At the end of the observation period, an accumulation of macrophages and calcification was observed in the media and endothelial cells reappeared at the graft surface. The findings demonstrate major cellular and structural changes in the transplanted artery, including activation, proliferation and apoptosis of SMCs, and an altered composition of the extracellular matrix. Possibly, the observed changes in SMC phenotype, cell cycle and apoptosis during development of transplant arteriosclerosis are related to the expression of extracellular matrix proteins.
Mol Cell Biochem 2003 Jul
PMID:Arteriosclerosis in rat aortic allografts: dynamics of cell growth, apoptosis and expression of extracellular matrix proteins. 1295 1

Osteopontin (OPN) is a secreted phosphoprotein that has been associated with malignancy of breast and other cancers. OPN binds to several cell surface integrins including alpha(v)beta(3), alpha(v)beta(5), and alpha(v)beta(1). Although the relative contribution of these integrins to breast cancer cell malignancy is uncertain, correlative studies suggest that alpha(v)beta(3) may be particularly associated with increased tumor aggressiveness. Previously, we reported that tumorigenic, nonmetastatic 21NT mammary carcinoma cells respond to OPN through alpha(v)beta(5) and alpha(v)beta(1) but not alpha(v)beta(3). Here, we determined that 21NT cells lack beta(3) expression, and we asked whether expression of alpha(v)beta(3) could enhance the ability of breast cancer cells to respond to the malignancy-promoting effects of OPN both in vitro and in vivo. 21NT cells stably transfected with beta(3) showed significantly increased adhesion, migration, and invasion to OPN in vitro compared with vector control. To determine if beta(3) could also enhance the response of breast epithelial cells to OPN in vivo, cells stably transfected with both beta(3) and OPN (NT/Obeta(3)) were injected into the mammary fat pad of female nude mice and primary tumor growth was assessed relative to controls. Mice injected with NT/Obeta(3) cells demonstrated a significantly increased primary tumor take (75% of mice) compared with controls (0-12.5% of mice) as well as a decreased tumor doubling time and a decreased tumor latency period. These results suggest that increased expression of the alpha(v)beta(3) integrin during breast cancer progression can make tumor cells more responsive to malignancy-promoting ligands such as OPN and result in increased tumor cell aggressiveness.
Mol Cancer Res 2003 Sep
PMID:Beta(3) integrin expression increases breast carcinoma cell responsiveness to the malignancy-enhancing effects of osteopontin. 1451 43

Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-beta(1) and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis.
Am J Physiol Lung Cell Mol Physiol 2004 Jun
PMID:Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. 1497 30

The orphan nuclear receptor Nurr1 is mainly expressed in the central nervous system but is also detected in certain peripheral tissues such as bone. To elucidate the role of Nurr1 in bone, we examined the ability of Nurr1 to regulate osteopontin (OPN) expression in osteoblastic cell lines. Transfection of Nurr1 in osteoblastic cells increased OPN mRNA expression. A dominant negative Nurr1 variant abolished the ability of PTH to induce OPN expression, suggesting that Nurr1 is involved in mediating the regulation of OPN by PTH. Nurr1 efficiently transactivated a luciferase reporter construct driven by the -857/+191 fragment of the mouse OPN promoter. The activation of the OPN promoter was mediated by the monomeric form of Nurr1, required direct binding of Nurr1 to the OPN promoter, and was dependent on the amino-terminal transactivation function-1. The OPN promoter is also regulated by vitamin D receptor and estrogen-related receptors. We show that Nurr1 and vitamin D activate the OPN promoter in a synergistic fashion, whereas Nurr1-mediated transactivation of the OPN promoter is repressed by estrogen-related receptors. In conclusion, Nurr1 activates the OPN promoter directly in osteoblastic cells, suggesting a role for Nurr1 in the regulation of bone homeostasis.
Mol Endocrinol 2004 Jun
PMID:Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts. 1498 26


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