There is substantial evidence that Kaposi sarcoma-associated herpesvirus (KSHV) plays an important role in the pathogenesis of all forms of Kaposi sarcoma (KS). It has been noted that KS commonly occurs in locations, such as the feet, where tissue may be poorly oxygenated. On the basis of this observation, the potential role of hypoxia in the reactivation of KSHV replication was explored by studying 2 KSHV-infected primary effusion lymphoma B-cell lines (BC-3 and BCBL-1) latently infected with KSHV. Acute and chronic exposure of these cells to hypoxia (1% O 2 ) induced KSHV lytic replication, as indicated by an increase in intracellular lytic protein expression and detection of virus in cell supernatants by Western immunoblotting. In addition, hypoxia increased the levels of secreted viral interleukin-6. Moreover, hypoxia enhanced the lytic replication initiated by the viral inducer 12-O-tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride, 2 compounds that increase the intracellular levels of hypoxia-inducible factor 1, were also able to induce KSHV lytic replication. These studies suggest that hypoxia is an inducer of KSHV replication. This process may play an important role in the pathogenesis of KS. ( IntroductionKaposi sarcoma (KS) is a multifocal proliferative disease of vascular origin. KS lesions are characterized by proliferation and growth of spindle-shaped neoplastic cells that appear to be of lymphatic endothelial cell origin. [1][2][3] KS is the most common neoplasm in human immunodeficiency virus type 1-infected individuals. 1 Even before the advent of acquired immunodeficiency syndrome (AIDS), KS was known to be more prevalent in certain geographic areas and groups of patients (classic and endemic KS). A classic form of KS is described as occurring in elderly men in southern Italy and other Mediterranean countries, 4 and an endemic form of KS has been observed to occur in sub-Saharan Africa. 5,6 In addition, transplant recipients and other immunosuppressed patients are at risk for developing KS. 4 Since the discovery of Kaposi sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), in 1994, 7 substantial evidence has been accumulated that implicates it as an essential factor in the pathogenesis of all forms of KS. 8,9 It is also involved in the pathogenesis of primary effusion lymphoma (PEL) and certain cases of multicentric Castleman disease. 10 KSHV DNA is detected in nearly all KS lesions. 7,11,12 As with other human herpesviruses, infection with KSHV can be latent or lytic. Activation of viral replication in latently infected B cells, endothelial cells, or other target cells may be responsible for viral spread and contribute to the development of KS. 4 KSHV encodes for several cellular gene mimics that are produced during lytic replication and that have proangiogenic activity. [13][14][15][16] The virus also encodes several cellular protein mimics with oncogenic potential, such as v-cyc, a D-type cyclin, and a member of the interferon regulatory factor ...
The transcriptome is extensively and dynamically regulated by a network of RNA modifying factors. RNA editing enzymes APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and ADAR (adenosine deaminase, RNA-specific) irreversibly recode primary RNA sequences, whereas newly described methylases (writers) and demethylases (erasers) dynamically alter RNA molecules in response to environmental conditions. RNA modifications can affect RNA splicing, nuclear-cytoplasmic transport, translation, and regulation of gene expression by RNA interference. In addition, tRNA base modifications, processing, and regulated cleavage have been shown to alter global patterns of mRNA translation in response to cellular stress pathways. Recent studies, some of which were discussed at this workshop, have rekindled interest in the emerging roles of RNA modifications in health and disease. On September 10th, 2014, the Division of Cancer Biology, NCI sponsored a workshop to explore the role of epitranscriptomic RNA modifications and tRNA processing in cancer progression. The workshop attendees spanned a scientific range including chemists, virologists, and RNA and cancer biologists. The goal of the workshop was to explore the interrelationships between RNA editing, epitranscriptomics, and RNA processing and the enzymatic pathways that regulate these activities in cancer initiation and progression. At the conclusion of the workshop, a general discussion focused on defining the major challenges and opportunities in this field, as well as identifying the tools, technologies, resources and community efforts required to accelerate research in this emerging area.
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