Molecular Characterization of Auxin Efflux Carrier- ABCB1 in hexaploid wheat

Auxin is an important phytohormone that regulates response, differentiation, and development of plant cell, tissue, and organs. Along with its local production, long-distance transport coordinated by the efflux/influx membrane transporters is instrumental in plant development and architecture. In the present study, we cloned and characterized a wheat (Triticum aestivum) auxin efflux carrier ABCB1. The TaABCB1 was physically localized to the proximal 15% of the short arm of wheat homoeologous group 7 chromosomes. Size of the Chinese spring (CS) homoeologs genomic copies ranged from 5.3–6.2 kb with the 7A copy being the largest due to novel insertions in its third intron. The three homoeologous copies share 95–97% sequence similarity at the nucleotide, 98–99% amino acid, and overall Q-score of 0.98 at 3-D structure level. Though detected in all analyzed tissues, TaABCB1 predominantly expressed in the meristematic tissues likely due to the presence of meristem-specific activation regulatory element identified in the promoter region. RNAi plants of TaABCB1 gene resulted in reduced plant height and increased seed width. Promoter analysis revealed several responsive elements detected in the promoter region including that for different hormones as auxin, gibberellic acid, jasmonic acid and abscisic acid, light, and circadian regulated elements.

Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

Differentiation of Promonocytic U937 Cells to Monocytes Is Associated with Reduced Mitochondrial Transport of Ascorbic Acid

Growth of promonocytic U937 cells in the presence of DMSO promotes their differentiation to monocytes. After 4 days of culture in differentiating medium, these cells ceased to proliferate, displayed downregulated ryanodine receptor expression, and responded to specific stimuli with enhanced NADPH-oxidase-derived superoxide formation or cytosolic phospholipase A2-dependent arachidonic acid release. We found that the 4-day differentiation process is also associated with downregulated SVCT2 mRNA expression, in the absence of apparent changes in SVCT2 protein expression and transport rate of ascorbic acid (AA). Interestingly, under the same conditions, these cells accumulated lower amounts of the vitamin in their mitochondria, with an ensuing reduced response to external stimuli sensitive to the mitochondrial fraction of AA. Further analyses demonstrated an unexpected increase in mitochondrial SVCT2 protein expression, however, associated with reduced SVCT2-dependent AA uptake in isolated mitochondria. A decrease in the transporter Vmax, with no change in affinity, was found to account for this response. Differentiation of promonocytic cells to monocytes is therefore characterized by decreased SVCT2 mRNA expression that, even prior to the onset of SVCT2 protein downregulation or apparent changes in plasma membrane transport activity, impacts on the mitochondrial accumulation of the vitamin through a decreased Vmax of the transporter.

Treating a Dysregulated JAK/STAT Pathway in Cancer Cells

The JAK/STAT pathway is induced by the binding of a cytokine to its cognate receptor. The receptor’s engagement with the cytokine recruits a JAK protein, which activates itself via auto/trans-phosphorylation. In turn, the activated JAKs recruit and phosphorylate STAT proteins. The phosphorylated STAT proteins form a dimer, translocate to the cell nucleus and acts as a transcription factor to induce gene expression. In this way, the JAK/STAT pathway can mediate a cell’s response to extracellular signals. The proteins ultimately induced by the JAK/STAT pathway contribute to processes such as inflammatory response, differentiation, proliferation, and apoptosis. When the JAK/STAT pathway becomes dysregulated, proto-oncogenes and/or tumor-suppressor genes are often inappropriately expressed, commonly resulting in oncogenesis. This review discusses how SOCS, PIAS, and PTPS proteins modulate the JAK/STAT pathway ensuring that it remains cyclic and transient. The use of jakibins, STAT inhibitors, decoy oligonucleotides, RNA interference and genome editing to synthetically regulate a dysregulated JAK/STAT pathway in cancer cells are also considered.