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MAPK signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Archana Devi, Bhavana Kushwaha, Gopal Gupta
The pathway architecture involves a small G protein (RAS) and three protein kinases (RAF, MEK, ERK). The pathway commences with the binding of a ligand to the transmembrane receptor, which is a receptor tyrosine kinase (RTK). The signaling cascade finally results in the translocation of ERK to the nucleus where ERK transactivates different transcription factors that lead to the expression of specific genes to complete the cellular response (18). Furthermore, MAPKs orient with scaffold proteins to create a supportive environment to facilitate their interaction with specific proteins and substrates. Various protein phosphatases mediate the regulation of MAPK activity, the culmination of MAPK signaling. Such protein phosphatases dephosphorylate crucial proteins in the MAPK signaling and regulate the scale and extent of signaling (19,20).
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
In addition, TORC1 enhances the translation of a different set of RNAs by phosphorylating 4E-BP1 (2,6). eIF4E is a component of a helicase complex that binds to the 7-methylguanine cap at the 5′ end of mRNAs and enhances the ability of ribosome-eIF complexes to scan the mRNA for initiation sites. 4E-BP1, in its unphosphorylated state, binds to eIF4E and inhibits the eIF4E-containing helicase complex. Activation of TORC1 signaling causes hyperphosphorylation of 4E-BP1, diminishing the stability of the 4E-BP1/eIF4E complex, and causing its dissociation. Free eIF4E then binds to the scaffold protein eIF4G and the RNA helicase eIF4A, forming an active helicase that facilitates translation of mRNAs containing long, highly folded 5′ untranslated regions. Included in this class of transcripts are messages encoding cyclin D1, c-Myc, hypoxia inducible factor-lα (HIF-lα), vascular endothelial growth factor and fibroblast growth factor as well as ribosomal proteins themselves (2,3,6). These molecules are not only critical for cell survival and proliferation, but also have the potential to be used to monitor therapy. Because HIF-lα regulates the glycolytic pathway and fluorodeoxyglucose positron emission tomography (FDG-PET) detects tumors by their elevated rates of glycolysis, FDG-PET can potentially be used to assess inhibition of this pathway after treatment with mTOR inhibitors (2,3).
The Anticancer Potential of the Bacterial Protein Azurin and Its Derived Peptide p28
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Ana Rita Garizo, Nuno Bernardes, Ananda M. Chakrabarty, Arsénio M. Fialho
There are many reasons that support the theory that azurin has the potential to act as an anticancer agent. Besides its preferential entry into cancer cells, no adverse side effects were observed in in vivo studies [11, 51, 52]. As mentioned above, this protein also can mediate specific high-affinity interactions with various unrelated mammalian proteins relevant in cancer, conferring on it the property of a natural scaffold protein, which is probably the most important characteristic of this protein [17]. This ability to act on multiple targets is important since it might be harder to trigger resistance by the cells. Another advantage of this bacterial protein is that azurin is a water-soluble molecule with a hydrophobic patch and this might help in its tissue penetration and clearance from the bloodstream [9]. In addition to all this, azurin can be easily hyperexpressed in Escherichia coli, which makes the process of production very cheap [15]. All these reasons make azurin an attractive molecule to be used in cancer therapy.
Asymmetric distribution of dynamin-2 and β-catenin relative to tight junction spikes in alveolar epithelial cells
Published in Tissue Barriers, 2021
K. Sabrina Lynn, Kristen F. Easley, Francisco J. Martinez, Ryan C. Reed, Barbara Schlingmann, Michael Koval
Adherens junctions and tight junctions both interact with the actin cytoskeleton, specifically through scaffold proteins such as catenins and ZO-1, respectively.26–29 To visualize co-localization of these proteins with the actin cytoskeleton, we double labeled AECs with Alexa 405-phalloidin, labeling actin, along with either anti-β-catenin or anti-ZO-1 (Figure 5). AECs had prominent actin filaments that radiated from a central point in the interior of the cell, that co-localized with β-catenin at the terminal ends (Figure 5(a)). Tight junction spikes also co-localized with radiating actin filaments, with spikes projecting along actin filaments toward the cell interior (Figure 5(b)). In addition to actin filaments, we observed faintly visible cortical actin that co-localized with ZO-1 at AEC tight junctions as previously described.19
Development of Bioengineered Organ Using Biological Acellular Rat Liver Scaffold and Hepatocytes
Published in Organogenesis, 2020
Tanya Debnath, Chandra Shekar Mallarpu, Lakshmi Kiran Chelluri
Solid organ regeneration is an emerging area in tissue engineering, providing tissue constructs with functional remodeling, and potential to re-integrate into host systems.1 Recent tissue engineering approaches provide biological scaffolds composed of extracellular matrix (ECM) controlling cell functions and promoting new tissue formation. Biomaterials were employed as scaffolds for the incorporation of required cell types which intrinsically modulate the tissue microenvironment. Various natural biopolymers have been used as scaffolds to mimic the extra cellular matrix of the tissues in vitro. Our previous study exhibited that these biopolymer-based scaffolds in a three-dimensional (3D) culture systems conserve the cell phenotype and support their proliferation.2,3 The biological signaling for cell adhesion and proliferation is constantly regulated by the scaffold proteins which are being modulated based on the metabolic and functional requirements of the healthy tissues and organ.4 Intact three-dimensional extracellular matrices from different allogeneic and xenogeneic tissue sources are known to preserve the cellular phenotypes with the help of obligatory ligands and bioactive molecules during the process of tissue regeneration.5,6 Further, the natural ECM of the tissues is advantageous over conventional two-dimensional and three-dimensional culture systems, as they maintain and retain the complex microstructure and functional proteins.7
The Antibody Society’s antibody validation webinar series
Published in mAbs, 2020
Jan L.A. Voskuil, Anita Bandrowski, C. Glenn Begley, Andrew R.M. Bradbury, Andrew D. Chalmers, Aldrin V. Gomes, Travis Hardcastle, Fridtjof Lund-Johansen, Andreas Plückthun, Giovanna Roncador, Alejandra Solache, Michael J. Taussig, James S. Trimmer, Cecilia Williams, Simon L. Goodman
Several affinity binders based on scaffold proteins have been designed and used as alternatives to antibodies,33 including Adnectins, Affibodies, Affimers, Anticalins, Bicyclic peptides, DARPins, Fynomers, Kunitz domains, and Monobodies. The general concept for each is similar: a stable scaffold protein is used to display diversified amino acid sequences at exposed surface sites, and the affinity binders are selected using an appropriate display platform (phage, yeast or ribosome display). Because of the small size and their low-cost production, such alternatives to antibodies are being evaluated in clinical trials,33 and will likely soon enter the commercial tool affinity binder market. As with antibodies, validation for specific purposes and batch quality control remain necessary.