epidermal-growth-factor and Sarcoma--Kaposi

Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway has been associated with a variety of tumors, including AIDS-related KS. The oncoprotein Raf is situated at a pivotal position in regulating the MAPK pathway. Hence, we analysed the effect of oncoprotein Raf on HHV-8 infectious entry into target cells. Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis.

Topics: AIDS-Related Opportunistic Infections; Blotting, Western; Butadienes; Cell Line; Enzyme Activation; Enzyme Inhibitors; Epidermal Growth Factor; Estradiol; Green Fluorescent Proteins; Heparin-binding EGF-like Growth Factor; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Intercellular Signaling Peptides and Proteins; Luminescent Proteins; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Nitriles; Proto-Oncogene Proteins c-raf; Receptors, Estrogen; Recombinant Fusion Proteins; Sarcoma, Kaposi; Signal Transduction; Vascular Endothelial Growth Factor A

We have investigated the mitogenicity of Epidermal Growth Factor (EGF) and Transforming Growth Factor alpha (TGF-alpha) for cultured Kaposi's sarcoma derived cells (KS cells). In contrast to control fibroblasts from the same patients, KS cells revealed only a weak mitogenic response to these growth factors. Neither EGF nor TGF-alpha were able to substitute for Platelet-derived growth factor (PDGF) when KS cells were grown in PDGF-depleted Platelet-Poor-Plasma serum (PPPS)-supplemented medium. The low mitogenicity of EGF and TGF-alpha for KS cells is not based upon a reduced expression of EGF receptor mRNA and protein in KS cells. However, the binding of EGF to KS cells is about 50% lower than that to fibroblasts. This reduced binding is not due to an occupation of the receptors by TGF-alpha since the expression level of this mitogen in different KS cell lines does not correlate with their capacity to bind EGF. In contrast, the low EGF binding seems to be an intrinsic feature of the EGF receptors of KS cells. In spite of the low mitogenicity of EGF for the tumor cells, the expression of c-myc, PDGF-A and Fibroblast growth factor 5 (FGF-5) mRNA is equally induced by purified EGF in KS cells and fibroblasts. This shows that at least the signal transduction pathways which lead to the expression of these genes are functional in KS cells.

Topics: Blotting, Northern; Epidermal Growth Factor; ErbB Receptors; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Mitosis; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-myc; RNA, Messenger; Sarcoma, Kaposi; Signal Transduction; Transforming Growth Factor alpha; Tumor Cells, Cultured