Recombination studies have established that retroviral long terminal repeats (LTRs) are important genetic determinants of the viral capacity to induce hematopoietic tumors and to specify the type of cell making up the tumor. Plasmids containing LTRs of several murine leukemia viruses linked to the chloramphenicol acetyltransferase gene were tested in transient assays to measure relative rates of transcriptional activity in different types of hematopoietic cells. LTRs of the thymomagenic viruses SL3-3, Moloney leukemia virus, and a Moloney mink cell focus-forming virus all expressed to higher levels than other LTRs in T-lymphocyte cell lines. Conversely, the LTRs of Friend leukemia virus and a polycythemic spleen focus-forming virus expressed to higher levels than other LTRs in erythroleukemia cells. The LTR of nonleukemogenic Akv virus induced a relatively low level of activity compared with the others in all cells tested. Thus the relative level of LTR-driven expression in various types of cells corresponds to the type of tumor caused by the intact virus in vivo. These results provide direct evidence that the tissue specificity of the transcriptional activity of LTRs plays a critical role in determining the target cell for retroviral oncogenesis.
The cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene is expressed in multiple tissues and is regulated in a complex tissue-specific manner. To map the cis-acting DNA elements that direct this tissue-specific expression, we made transgenic mice containing truncated PEPCK-human growth hormone (hGH) fusion genes. The transgenes contained PEPCK promoter fragments with 5' endpoints at -2088, -888, -600, -402, and -207 bp, while the 3' endpoint was at +69 bp. Immunohistochemical analysis showed that the -2088 transgene was expressed in the correct cell types (hepatocytes, proximal tubular epithelium of the kidney, villar epithelium of the small intestine, epithelium of the colon, smooth muscle of the vagina and lungs, ductal epithelium of the sublingual gland, and white and brown adipocytes). Solution hybridization of hGH mRNA expressed from the transgenes indicated that white and brown fat-specific elements are located distally (-2088 to -888 bp) and that liver-, gut-, and kidney-specific elements are located proximally (-600 to +69 bp). However, elements outside of the region tested are necessary for the correct developmental pattern and level of PEPCK expression in kidney. Both the -2088 and -402 transgenes responded in a tissue-specific manner to dietary stimuli, and the -2088 transgene responded to glucocorticoid stimuli. Thus, different tissues utilize distinct cell-specific cis-acting elements to direct and regulate the PEPCK gene.Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), an enzyme that catalyzes the conversion of oxaloacetic acid to phosphoenolpyruvate, performs a variety of important tissue-specific metabolic roles in mammals (21,30,58,68,70). For example, it is rate limiting for gluconeogenesis in hepatocytes and in proximal tubular epithelia of the kidney, is also ammoniagenic in the kidney, and is glyceroneogenic in white adipocytes. In addition to being present in liver, kidney, and white fat, PEPCK is found in similar amounts in brown fat, intestinal epithelium, and mammary gland, though its function has not been investigated in the latter three tissues (1,22,75). Lesser amounts of PEPCK have been reported in colon, heart, skeletal muscle, lung, ovary, certain smooth muscles, and sublingual gland, where its function is also not known (30,75).Regulation of PEPCK is complex, as it is expressed in multiple cell types and changes in response to multiple hormones, environmental factors, cell-cell interactions, and development (5,7,11,15,24,43,45,54,68,69,71,72 (14, 24, 39, 42, 43, 46-48, 63, 68, 74) (14,24,39,42,43,63,74). Glucocorticoids are also inducers in kidney, as are hydrogen ions (acidosis), while cAMP and insulin are weak effectors (47). In contrast, glucocorticoids inhibit transcription of the PEPCK gene in adipocytes (48). The PEPCK gene is also developmentally regulated (for a review, see reference 23) and has been well characterized in rat liver, where it is competent but dormant as much as 6 days prior to birth but is induced at parturition in response to chang...
The prevalence, natural history, and genetic characteristics of simian immunodeficiency virus (SIV) infections in most feral African monkey species are presently unknown, yet this information is essential to elucidate their origin and relationship to other simian and human immunodeficiency viruses. In this study, a combination of classical and molecular approaches were used to identify and characterize SIV isolates from West African green monkeys (Cercopithecus sabaeus) (SIVagm isolates). Four SIVagm viruses from wildcaught West African green monkeys were isolated and analyzed biologically and molecularly. Amplification, cloning, and sequencing of a 279-bp polymerase fragment directly from uncultured peripheral blood mononuclear cells was facilitated by the use of nested polymerase chain reaction. The results indicated that West African green monkeys are naturally infected with SIVs which are closely related to East African SIVagm isolates. However, structural, antigenic, and genetic differences were observed which strongly suggest that the West African green monkey viruses comprise a phylogenetically distinct subgroup of SIVagm. These findings support our previous hypothesis that SIVagm viruses may have evolved and diverged coincident with the evolution and divergence of their African green monkey host. In addition, this study describes a polymerase chain reaction-based approach that allows the identification and molecular analysis of divergent SIV strains directly from primary monkey tissue. This approach, which does not depend on virus isolation methods, should facilitate future studies aimed at elucidating the origins and natural history of SIVs in feral African green monkey populations.
Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...
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