Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha.
 ...
PMID:Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors. 806 19

Cementum-derived attachment protein (CAP) is a Mr 56,000 collagenous protein which promotes the adhesion and spreading of mesenchymal cell types. The CAP promotes the adhesion of osteoblasts and periodontal ligament cells better than gingival fibroblasts, while epithelial cells do not adhere to CAP-coated surfaces. To understand the mechanisms involved in CAP action, we have studied the signal transduction events induced by the CAP in human fibroblasts during cell adhesion. Human gingival fibroblasts were serum starved for 48 h, trypsinized, and added to non-tissue culture plastic plates previously coated with CAP. At various time points, attached cells were examined for induction of signaling reactions. Adherence of cells to plates coated with CAP caused tyrosine phosphorylation of proteins migrating on PAGE with molecular mass of 125-130, 85, 70, and 42-44 kDa. We identified focal adhesion kinase p125FAK and p130Cas as components of the 125-130 kDa protein band; however, p125FAK was the major phosphorylated component. ERK-1 and ERK-2 were detected in the 42-44 kDa protein band, but only the ERK-2, not ERK-1, was phosphorylated. Adhesion to CAP-stimulated mitogen-activated protein kinase (MAPK) activity and induced the expression of c-fos mRNA. Protein-tyrosine phosphorylation and c-fos mRNA expression were not induced in unattached cells, and adhesion was not abolished by the protein tyrosine kinase inhibitor, genestein. MAPK activity and c-fos mRNA expression were not induced in monolayer cultures, indicating that these reactions are induced by adhesion and not necessary for cell adhesion. The kinetics of MAPK activation were different from cells attaching on fibronectin (FN) or polylysine, and c-fos mRNA levels increased only half as much on FN and very little on polylysine. These data demonstrated that CAP and other adhesion molecules present in mineralized tissue matrices induce characteristic signaling events during adhesion, which may play a role in recruitment of specific cell types during wound healing and in mediating their specific biological functions.
 ...
PMID:Signaling reactions induced in human fibroblasts during adhesion to cementum-derived attachment protein. 989 67

E-selectin, a cytokine-inducible adhesion molecule, supports rolling and stable arrest of leukocytes on activated vascular endothelium. Previous studies have suggested that this transmembrane protein can also transduce signals into the endothelial cell. We now demonstrate activation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured HUVEC in response to E-selectin-dependent leukocyte adhesion and Ab-mediated cross-linking of cell surface E-selectin. Adhesion of increasing numbers of HL60 cells to IL-1beta-activated HUVEC stimulated robust increases in MAPK activity that were abrogated by an E-selectin blocking Ab. Cross-linking of cell surface E-selectin with Abs, as a mimic of multivalent ligand engagement, strongly stimulated MAPK/extracellular signal-related kinase (ERK) kinase (MEK)-dependent MAPK activation and concomitant up-regulation of mRNA for c-fos, an immediate early response gene, whereas Ab cross-linking of HLA class I molecules (present at comparable density) failed to do so. Coimmunoprecipitation documented Ras, Raf-1 and, phospho-MEK complex formation. Unactivated HUVEC transduced with a full-length adenoviral E-selectin construct also exhibited cross-link-induced MAPK activation, macromolecular complex formation, and c-fos up-regulation, whereas HUVEC transduced with a cytoplasmic domain deletion mutant failed to respond. These observations indicate that E-selectin can transduce an activating stimulus via the MAPK cascade into the endothelial cell during leukocyte adhesion.
 ...
PMID:E-selectin-dependent signaling via the mitogen-activated protein kinase pathway in vascular endothelial cells. 1092