p53: The Multifaceted Roles of Covalent Modifications in Cancer.

The p53 protein has attracted huge research interest over several decades due to its role as one of the most important tumor suppressors in mammals, which orchestrates a synchronous response from normal cells in the body to various forms of stress. The diverse cellular activities of the p53 protein are regulated mainly via its post-translational modifications (PTMs). PTMs affect p53 on several levels: at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes, at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes; at the level of proteolysis in the absence of stress; and on the contrary, at the level of augmented protein stability in response to stress signals.

Lipoxygenases at the Intersection of Infection and Carcinogenesis.

The persisting presence of opportunistic pathogens like poses a significant threat to many immunocompromised cancer patients with pulmonary infections. This review highlights the complexity of interactions in the host's defensive eicosanoid signaling network and its hijacking by pathogenic bacteria to their own advantage. Human lipoxygenases (ALOXs) and their mouse counterparts are integral elements of the innate immune system, mostly operating in the pro-inflammatory mode.

Oncogenic BRCA1,2 Mutations in the Human Lineage-A By-Product of Sexual Selection?

In this review, we discuss the long-known problem of tissue-specific carcinogenesis in BRCA1 and BRCA2 mutation carriers: while the genes are expressed ubiquitously, increased cancer risk is observed mostly in the breast and ovaries, and to a much lesser extent, in some other tissues such as the prostate or pancreas. We reevaluate hypotheses on the evolutionary origin of these mutations in humans. Also, we align together the reports that at least some great apes have much lower risks of epithelial cancers in general and breast cancer in particular with the fact that humans have more voluminous breast tissue as compared to their closest extant relatives, particularly chimpanzees and bonobos.

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment.

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context.

Arachidonic acid: reconciling the dichotomy of its oxidative cascade through specific deuteration.

A new approach to attenuating pathological inflammatory reactions by buffering the eicosanoid pathways with oxidation-resistant hexadeuterated arachidonic acid (D-ARA) is discussed. Enzymatic processing of ARA, released by phospholipase A2, by lipoxygenases, cyclooxygenases, and cytochromes yields a wide range of bioactive eicosanoids, including pro-inflammation, pro-angiogenesis and pro-thrombosis species that, when produced in excess, are an underlying cause of pathology. Conversely, some products of ARA oxidation possess pro-resolving properties.

Flaviviruses in AntiTumor Therapy.

Oncolytic viruses offer a promising approach to tumor treatment. These viruses not only have a direct lytic effect on tumor cells but can also modify the tumor microenvironment and activate antitumor immunity. Due to their high pathogenicity, flaviviruses have often been overlooked as potential antitumor agents.

Non-Immunoglobulin Synthetic Binding Proteins for Oncology.

Extensive application of technologies like phage display in screening peptide and protein combinatorial libraries has not only facilitated creation of new recombinant antibodies but has also significantly enriched repertoire of the protein binders that have polypeptide scaffolds without homology to immunoglobulins. These innovative synthetic binding protein (SBP) platforms have grown in number and now encompass monobodies/adnectins, DARPins, lipocalins/anticalins, and a variety of miniproteins such as affibodies and knottins, among others. They serve as versatile modules for developing complex affinity tools that hold promise in both diagnostic and therapeutic settings.

BRCA Mutations-The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers.

Two related tumor suppressor genes, and , attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known.

Eutherian-Specific Functions of BetaM Acquired through Gene Co-Option in the Regulation of MyoD Expression.

Vertebrate genes represent a rare instance of orthologous gene co-option, resulting in radically different functions of the encoded BetaM proteins. In lower vertebrates, BetaM is a Na, K-ATPase β-subunit that is a component of ion pumps in the plasma membrane. In placental mammals, BetaM lost its ancestral role and, through structural alterations of the N-terminal domain, became a skeletal and cardiac muscle-specific protein of the inner nuclear membrane, highly expressed during late fetal and early postnatal development.

Artificial genetic polymers against human pathologies.

Originally discovered by Nielsen in 1991, peptide nucleic acids and other artificial genetic polymers have gained a lot of interest from the scientific community. Due to their unique biophysical features these artificial hybrid polymers are now being employed in various areas of theranostics (therapy and diagnostics). The current review provides an overview of their structure, principles of rational design, and biophysical features as well as highlights the areas of their successful implementation in biology and biomedicine.

Anti-cancer Virotherapy in Russia: Lessons from the Past, Current Challenges and Prospects for the Future.

The idea of using the lytic power of viruses against malignant cells has been entertained for many decades. However, oncolytic viruses gained broad attention as an emerging anti-cancer therapy only recently with the successful implementation of several oncolytic viruses to treat advanced melanoma. Here we review the history of oncolytic viruses in the Russian Federation and recent biotechnological advances in connection with the perspectives of their practical use against aggressive tumors such as glioblastoma or pancreatic cancer.

Deuterated Arachidonic Acid Ameliorates Lipopolysaccharide-Induced Lung Damage in Mice.

Arachidonic acid (ARA) is a major component of lipid bilayers as well as the key substrate for the eicosanoid cascades. ARA is readily oxidized, and its non-enzymatic and enzymatic oxidation products induce inflammatory responses in nearly all tissues, including lung tissues. Deuteration at bis-allylic positions substantially decreases the overall rate of ARA oxidation when hydrogen abstraction is an initiating event.

Properties of a cryptic lysyl oxidase from haloarchaeon .

Background: Lysyl oxidases (LOX) have been extensively studied in mammals, whereas properties and functions of recently found homologues in prokaryotic genomes remain enigmatic.

Methods: LOX open reading frame was cloned from in an expression vector. Recombinant lysyl oxidase (HTU-LOX) proteins were purified using metal affinity chromatography under denaturing conditions followed by refolding.

Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors.

Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes.

Mineralocorticoids modulate the expression of the β-3 subunit of the Na, K-ATPase in the renal collecting duct.

Renal sodium reabsorption depends on the activity of the Na,K-ATPase α/β heterodimer. Four α (α) and 3 β (β) subunit isoforms have been described. It is accepted that renal tubule cells express α/β dimers.

A strong developmental isotope effect in Caenorhabditis elegans induced by 5,5-deuterated lysine.

Effects exerted by heavy isotope substitution in biopolymers on the functioning of whole organisms have not been investigated. We report on the decrease of permissive temperature of nematodes fed with bacteria containing 5,5-D2-lysine. We synthesized 5,5-dideuterolysine and, taking advantage of lysine being an essential amino acid, showed that C.

Evolutionary diversification of the BetaM interactome acquired through co-option of the ATP1B4 gene in placental mammals.

ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that radically changed properties of the encoded BetaM proteins, which function as Na,K-ATPase subunits in lower vertebrates and birds. Eutherian BetaM has lost its ancestral function and became a muscle-specific resident of the inner nuclear membrane. Our earlier work implicated BetaM in regulation of gene expression through direct interaction with the transcriptional co-regulator SKIP.

Nuclear translocation of lysyl oxidase is promoted by interaction with transcription repressor p66β.

Lysyl oxidase (LOX) is an amine oxidase involved in protein cross-linking of the extracellular matrix. Less well characterized is the role that LOX plays among nuclear proteins, and molecular mechanisms of its transport to the nucleus are currently unknown. Here, we have employed yeast two-hybrid library screening and found that the LOX catalytic domain interacts with the transcription repressor p66β.

Two distinct nuclear localization signals in mammalian MSL1 regulate its function.

MSL1 protein regulates global histone H4 acetylation at residue K16 in stem and cancer cells, through interaction with KAT8. The functional significance of mammalian MSL1 isoforms, involved in various protein interactions, is poorly understood. We report the identification of a novel nuclear localization signal (NLS), common to all MSL1 isoforms, in addition to previously known bipartite NLS, located in domain PEHE.

Postnatal regulation of X,K-ATPases in rat skin and conserved lateroapical polarization of Na,K-ATPase in vertebrate epidermis.

Development of epidermis creates stratified epithelium with different sets of ion-transporting enzymes in its layers. We have characterized expression of Na,K- and H,K-ATPase α and β subunits and FXYD isoforms in rat skin. Maturation of rat skin from newborn to adult is associated with an increase in FXYD4 and a decrease of Na,K-ATPase α1-isoform, ATP1B4 and FXYD6 transcripts.

A link between fertility and K+ homeostasis: role of the renal H,K-ATPase type 2.

Renal K(+) retention is activated during pregnancy through a mechanism unknown to date. Here, we showed that the renal stimulation of H,K-ATPase type 2 (HKA2), whose expression was recently identified to be progesterone-dependent, is part of the mechanism favoring K(+) accumulation during gestation. Moreover, investigation of the gestational phenotype of HKA2-null mice compared to their wild-type (WT) littermate revealed a decrease in fertility (gestation was successful in 33 % of HKA2-null mice vs.

Structural evolution and tissue-specific expression of tetrapod-specific second isoform of secretory pathway Ca2+-ATPase.

Secretory pathway Ca-ATPases are less characterized mammalian calcium pumps than plasma membrane Ca-ATPases and sarco-endoplasmic reticulum Ca-ATPases. Here we report analysis of molecular evolution, alternative splicing, tissue-specific expression and subcellular localization of the second isoform of the secretory pathway Ca-ATPase (SPCA2), the product of the ATP2C2 gene. The primary structure of SPCA2 from rat duodenum deduced from full-length transcript contains 944 amino acid residues, and exhibits 65% sequence identity with known SPCA1.

Isolation and characterization of BetaM protein encoded by ATP1B4--a unique member of the Na,K-ATPase β-subunit gene family.

ATP1B4 genes represent a rare instance of the orthologous gene co-option that radically changed functions of encoded BetaM proteins during vertebrate evolution. In lower vertebrates, this protein is a β-subunit of Na,K-ATPase located in the cell membrane. In placental mammals, BetaM completely lost its ancestral role and through acquisition of two extended Glu-rich clusters into the N-terminal domain gained entirely new properties as a muscle-specific protein of the inner nuclear membrane possessing the ability to regulate gene expression.

Control of lysyl oxidase activity through site-specific deuteration of lysine.

Lysyl oxidase (LOX) is implicated in several extracellular matrix related disorders, including fibrosis and cancer. Methods of inhibition of LOX in vivo include antibodies, copper sequestration and toxic small molecules such as β-aminopropionitrile. Here, we propose a novel approach to modulation of LOX activity based on the kinetic isotope effect (KIE).

Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium.

Although the functional role of nicotinamide nucleotide transhydrogenase (Nnt) remains to be fully elucidated, there is strong evidence that Nnt plays a critical part in mitochondrial metabolism by maintaining a high NADPH-dependent GSH/GSSG ratio, and thus the control of cellular oxidative stress. Using real-time PCR, spectrophotometric and western blotting techniques, we sought to determine the presence, abundance and activity level of Nnt in human heart tissues and to discern whether these are altered in chronic severe heart failure. Left ventricular levels of the NNT gene and protein expression did not differ significantly between the non-failing donor (NF) and heart failure (HF) group.