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)

Normal fibroblasts are dependent on adhesion to a substrate for cell cycle progression. Adhesion-deprived Rat1 cells arrest in the G1 phase of the cell cycle, with low cyclin E-dependent kinase activity, low levels of cyclin D1 protein, and high levels of the cyclin-dependent kinase inhibitor p27kip1. To understand the signal transduction pathway underlying adhesion-dependent growth, it is important to know whether prevention of any one of these down-regulation events under conditions of adhesion deprivation is sufficient to prevent the G1 arrest. To that end, sublines of Rat1 fibroblasts capable of expressing cyclin E, cyclin D1, or both in an inducible manner were used. Ectopic expression of cyclin D1 was sufficient to allow cells to enter S phase in an adhesion-independent manner. In contrast, cells expressing exogenous cyclin E at a level high enough to overcome the p27kip1-imposed inhibition of cyclin E-dependent kinase activity still arrested in G1 when deprived of adhesion. Moreover, expression of both cyclins D1 and E in the same cells did not confer any additional growth advantage upon adhesion deprivation compared to the expression of cyclin D1 alone. Exogenously expressed cyclin D1 was down-regulated under conditions of adhesion deprivation, despite the fact that it was expressed from a heterologous promoter. The ability of cyclin D1-induced cells to enter S phase in an adhesion-independent manner disappears as soon as cyclin D1 proteins disappear. These results suggest that adhesion-dependent cell cycle progression is mediated through cyclin D1, at least in Rat1 fibroblasts.
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PMID:Ectopic expression of cyclin D1 but not cyclin E induces anchorage-independent cell cycle progression. 927 39

The tumor microenvironment is often overlooked when considering tumor response to chemotherapeutic agents. This environment consists of soluble factors, components of the extracellular matrix as well as cell-cell interactions. Recently, it has become clear that cell-cell and cell-matrix interactions result in cytoskeletal reorganization and the activation of multiple signal transduction pathways that directly influence cell survival, growth and differentiation. Experimental evidence shows that anti-apoptotic pathways initiated by cell adhesion are operative in tumor cells and, furthermore, cause resistance to mechanistically distinct cytotoxics. For hematopoietic tumors, cell adhesion to a single matrix, fibronectin is sufficient to inhibit apoptosis induced by mechanistically distinct cyctotoxics. Adhesion of hematopoietic tumors to this matrix blocks cell cycle progression, and for the human multiple myeloma 8226 cell line adhesion to fibronectin resulted in increased p27kip1 levels, which correlated with cell cycle arrest and drug resistance. A decrease in initial DNA damage induced by topoisomerase II inhibitors has also been observed in adherent hematopoietic tumor cell lines. Further studies investigating the mechanisms of cell adhesion mediated drug resistance may reveal novel targets directed at the reversal of de novo drug resistance.
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PMID:Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. 1183 46