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)

Mutations that lead to anchorage-independent survival are a hallmark of tumor cells. Adhesion of integrin receptors to extracellular matrix activates a survival signaling pathway in epithelial cells where Akt phosphorylates and blocks the activity of proapoptotic proteins such as the BCL2 family member Bad, the forkhead transcription factor FKHRL-1, and caspase 9. Insulin-like growth factor 1 (IGF-1) is a well-established epithelial cell survival factor that also triggers activation of Akt and can maintain Akt activity after cells lose matrix contact. It is not until IGF-1 expression diminishes (~16 h after loss of matrix contact) that epithelial cells deprived of matrix contact undergo apoptosis. This suggests that IGF-1 expression is linked to cell adhesion and that it is the loss of IGF-1 which dictates the onset of apoptosis after cells lose matrix contact. Here, we examine the linkage between cell adhesion and IGF-1 expression. While IGF-1 is able to maintain Akt activity and phosphorylation of proapoptotic proteins in cells that have lost matrix contact, Akt is not able to phosphorylate and inactivate another of its substrates, glycogen synthase kinase 3beta (GSK-3beta), under these conditions. The reason for this appears to be a rapid translocation of active Akt away from GSK-3beta when cells lose matrix contact. One target of GSK-3beta is cyclin D, which is turned over in response to this phosphorylation. Therefore, cyclin D is rapidly lost when cells are deprived of matrix contact, leading to a loss of cyclin-dependent kinase 4 activity and accumulation of hypophosphorylated, active Rb. This facilitates assembly of a repressor complex containing histone deacetylase (HDAC), Rb, and E2F that blocks transcription of the gene for IGF-1, leading to loss of Akt activity, accumulation of active proapoptotic proteins, and apoptosis. This feedback loop containing GSK-3beta, cyclin D, HDAC-Rb-E2F, and IGF-1 then determines how long Akt will remain active after cells lose matrix contact, and thus it serves to regulate the onset of apoptosis in such cells.
 ...
PMID:Transcriptional repression by RB-E2F and regulation of anchorage-independent survival. 1131 58

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
 ...
PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator--cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator--cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion-mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy.
 ...
PMID:Characterization of cyclin E expression in multiple myeloma and its functional role in seliciclib-induced apoptotic cell death. 2255 78