ABSTRACT
@#In recent decades cancer incidences and mortality rates have increased. Although there is significant progress in identifying the root causes and emerging therapies, there are many molecular, cellular mechanism’s unrevealed and current treatments have yet to deliver on their promises. Common characteristics of cancer that are controlled by various mechanisms, including those involving glycosylation-dependent proliferative signalling, the ability of tumor cells and their microenvironment to sustain proliferative signalling, enhancing the replicative immortality, evading the effects of growth suppressors, resisting apoptosis, sustaining invasion and metastasis, stimulation of angiogenesis and triggering immune response are few to name. An evolutionarily conserved family of glycan-binding proteins known as galectins has a significant impact in controlling these cascades. Galectins belong to animal lectin family that function by interacting with matrix glyco-proteins on extracellular surface and also with nuclear proteins modulating the cell signalling cascades intracellularly. In this review, we analyse how galectins influence the cellular pathways that control tumor activity, providing relevant examples and highlighting their therapeutic perspective in the fight against cancer.
ABSTRACT
We constructed a novel chicken (Gallus gallus) lung cDNA library fused inside yeast acting domain vector (pGADT7). Using yeast two-hybrid screening with highly pathogenic avian influenza (HPAI) nucleoprotein (NP) from the strain (A/chicken/Malaysia/5858/2004(H5N1)) as bait, and the Gallus gallus lung cDNA library as prey, a novel interaction between the Gallus gallus cellular RNA export adaptor protein Aly/REF and the viral NP was identified. This interaction was confirmed and validated with mammalian two hybrid studies and co-immunoprecipitation assay. Cellular localization studies using confocal microscopy showed that NP and Aly/REF co-localize primarily in the nucleus. Further investigations by mammalian two hybrid studies into the binding of NP of other subtypes of influenza virus such as the swine A/New Jersey/1976/H1N1 and pandemic A/Malaysia/854/2009(H1N1) to human Aly/REF, also showed that the NP of these viruses interacts with human Aly/REF. Our findings are also supported by docking studies which showed tight and favorable binding between H5N1 NP and human Aly/REF, using crystal structures from Protein Data Bank. siRNA knockdown of Aly/REF had little effect on the export of HPAI NP and other viral RNA as it showed no significant reduction in virus titer. However, UAP56, another component of the TREX complex, which recruits Aly/REF to mRNA was found to interact even better with H5N1 NP through molecular docking studies. Both these proteins also co-localizes in the nucleus at early infection similar to Aly/REF. Intriguingly, knockdown of UAP56 in A549 infected cells shows significant reduction in viral titer (close to 10 fold reduction). Conclusively, our study have opened new avenues for research of other cellular RNA export adaptors crucial in aiding viral RNA export such as the SRSF3, 9G8 and ASF/SF2 that may play role in influenza virus RNA nucleocytoplasmic transport.
