LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

ABSTRACT Epstein-Barr Virus (EBV) is a gammaherpesvirus that infects the majority of the human population and is linked to the development of multiple cancers, including nasopharyngeal carcinoma. Latent membrane protein 1 (LMP1) is considered the primary oncoprotein of EBV, and in epithelial cells it induces the expression and activation, or phosphorylation, of the epidermal growth factor receptor kinase. To identify effects on additional kinases, an unbiased screen of receptor tyrosine kinases potentially activated by LMP1 was performed. Using a protein array, it was determined that LMP1 selectively activates insulin-like growth factor 1 receptor (IGF1R). This activation takes place in fibroblast, epithelial, and nasopharyngeal cell lines that express LMP1 stably and transiently. Of note, LMP1 altered the phosphorylation, but not the expression, of IGF1R. The use of LMP1 mutants with defective signaling domains revealed that the C-terminal activating region 2 domain of LMP1 increased the mRNA expression and the secretion of the ligand IGF1, which promoted phosphorylation of IGF1R. IGF1R phosphorylation was dependent upon activation of canonical NF-κB signaling and was suppressed by IκBα and a dominant negative form of TRAF6. Inhibition of IGF1R activation with two small-molecule inhibitors, AG1024 and picropodophyllin (PPP), or with short hairpin RNA (shRNA) directed against IGF1R selectively reduced proliferation, focus formation, and Akt activation in LMP1-positive cells but did not impair LMP1-induced cell migration. Expression of constitutively active Akt rescued cell proliferation in the presence of IGF1R inhibitors. These findings suggest that LMP1-mediated activation of IGF1R contributes to the ability of LMP1 to transform epithelial cells. IMPORTANCE EBV is linked to the development of multiple cancers in both lymphoid and epithelial cells, including nasopharyngeal carcinoma. Nasopharyngeal carcinoma is a major cancer that develops in specific populations, with nearly 80,000 new cases reported annually. LMP1 is consistently expressed in early lesions and continues to be detected within 50 to 80% of these cancers at later stages. It is therefore of paramount importance to understand the mechanisms through which LMP1 alters cell growth and contributes to tumorigenesis. This study is the first to determine that LMP1 activates the IGF1R tyrosine kinase by regulating expression of the ligand IGF1. Additionally, the data in this paper reveal that specific targeting of IGF1R selectively impacts LMP1-positive cells. These findings suggest that therapies directed against IGF1R may specifically impair the growth of EBV-infected cells

A Variant in a MicroRNA complementary site in the 3' UTR of the KIT oncogene increases risk of acral melanoma.

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma

Management of service crops for the provision of ecosystem services in vineyards: A review

Service crops are crops grown with the aim of providing non-marketed ecosystem services, i.e. differing from food, fiber and fuel production. Vineyard soils face various agronomic issues such as poor organic carbon levels, erosion, fertility losses, and numerous studies have highlighted the ability of service crops to address these issues. In addition to their ability to increase soil organic matter and fertility, and reduce runoff and erosion processes, service crops provide a large variety of ecosystem services in vineyards such as weed control, pest and disease regulation, water supply, water purification, improvement of field trafficability and maintenance of soil biodiversity. However, associating service crops with grapevines may also generate disservices and impair grape production: competition for soil resources with the grapevine is often highlighted to reject such association. Consequently, vinegrowers have to find a balance between services and disservices, depending on local soil and climate conditions, on their objectives of grape production and on the nature and temporality of the ecosystem services they expect during the grapevine cycle. This study proposes a review of the services and disservices provided by service crops in vineyards, and a framework for their management. Vinegrowers’ production objectives and pedoclimatic constraints form the preliminary stage to consider before defining a strategy of service crop management. This strategy assembles management options such as the choice of species, its spatial distribution within the vineyard, the timing of its installation, maintenance and destruction. These management options, defined for both annual and long-term time scales, form action levers which may impact cropping system functioning. Finally, we underline the importance of implementing an adaptive strategy at the seasonal time scale. Such tactical management allows adapting the cropping system to observed climate and state of the biophysical system during the grapevine cycle, in order to provide targeted services and achieve satisfactory production objectives