ABSTRACT
Increased expression of Notch signaling pathway components is observed in Kaposi sarcoma (KS) but the mechanism underlying the manipulation of the canonical Notch pathway by the causative agent of KS, Kaposi sarcoma herpesvirus (KSHV), has not been fully elucidated. Here, we describe the mechanism through which KSHV directly modulates the expression of the Notch ligands JAG1 and DLL4 in lymphatic endothelial cells. Expression of KSHV-encoded vFLIP induces JAG1 through an NFkappaB-dependent mechanism, while vGPCR upregulates DLL4 through a mechanism dependent on ERK. Both vFLIP and vGPCR instigate functional Notch signalling through NOTCH4. Gene expression profiling showed that JAG1- or DLL4-stimulated signaling results in the suppression of genes associated with the cell cycle in adjacent lymphatic endothelial cells, indicating a role for Notch signaling in inducing cellular quiescence in these cells. Upregulation of JAG1 and DLL4 by KSHV could therefore alter the expression of cell cycle components in neighbouring uninfected cells during latent and lytic phases of viral infection, influencing cellular quiescence and plasticity. In addition, differences in signaling potency between these ligands suggest a possible complementary role for JAG1 and DLL4 in the context of KS.
Subject(s)
Calcium-Binding Proteins/physiology , Cell Cycle/genetics , Cell Cycle/physiology , Endothelium, Vascular/physiology , Herpesvirus 8, Human/physiology , Intercellular Signaling Peptides and Proteins/physiology , Lymphatic System/physiology , Membrane Proteins/physiology , Receptors, Notch/physiology , Sarcoma, Kaposi/virology , Adaptor Proteins, Signal Transducing , Endothelium, Vascular/cytology , Endothelium, Vascular/virology , Gene Expression Regulation, Viral , Herpesvirus 8, Human/genetics , Humans , Jagged-1 Protein , Lymphatic System/cytology , Lymphatic System/virology , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/physiology , RNA, Messenger/genetics , Receptor, Notch4 , Receptors, Notch/genetics , Sarcoma, Kaposi/genetics , Serrate-Jagged Proteins , Signal Transduction , Up-RegulationABSTRACT
BACKGROUND: Bone and soft tissue tumors represent a diverse group of neoplasms thought to derive from cells of the mesenchyme or neural crest. Histological diagnosis is challenging due to the poor or heterogenous differentiation of many tumors, resulting in uncertainty over prognosis and appropriate therapy. RESULTS: We have undertaken a broad and comprehensive study of the gene expression profile of 96 tumors with representatives of all mesenchymal tissues, including several problem diagnostic groups. Using machine learning methods adapted to this problem we identify molecular fingerprints for most tumors, which are pathognomonic (decisive) and biologically revealing. CONCLUSION: We demonstrate the utility of gene expression profiles and machine learning for a complex clinical problem, and identify putative origins for certain mesenchymal tumors.
