Role of EGF Receptor Regulatory Networks in the Host Response to Viral Infections

In this review article, we will first provide a brief overview of EGF receptor (EGFR) structure and function, and its importance as a therapeutic target in epithelial carcinomas. We will then compare what is currently known about canonical EGFR trafficking pathways that are triggered by ligand binding, versus ligand-independent pathways activated by a variety of intrinsic and environmentally induced cellular stresses. Next, we will review the literature regarding the role of EGFR as a host factor with critical roles facilitating viral cell entry and replication. Here we will focus on pathogens exploiting virus-encoded and endogenous EGFR ligands, as well as EGFR-mediated trafficking and signaling pathways that have been co-opted by wild-type viruses and recombinant gene therapy vectors. We will also provide an overview of a recently discovered pathway regulating non-canonical EGFR trafficking and signaling that may be a common feature of viruses like human adenoviruses which signal through p38-mitogen activated protein kinase. We will conclude by discussing the emerging role of EGFR signaling in innate immunity to viral infections, and how viral evasion mechanisms are contributing to our understanding of fundamental EGFR biology.

Examining the Osmotic Response of Acidihalobacter aeolianus after Exposure to Salt Stress

Acidihalobacter aeolianus is an acidophilic, halo-tolerant organism isolated from a marine environment near a hydrothermal vent, an ecosystem whereby levels of salinity and total dissolved salts are constantly fluctuating creating ongoing cellular stresses. In order to survive these continuing changes, the synthesis of compatible solutes—also known as organic osmolytes—is suspected to occur, aiding in minimising the overall impact of environmental instability. Previous studies on A. aeolianus identified genes necessary for the accumulation of proline, betaine and ectoine, which are known to act as compatible solutes in other halophilic species. In this study, the impact of increasing the osmotic stress as well as the toxic ion effect was investigated by subjecting A. aeolianus to concentrations of NaCl and MgSO4 up to 1.27 M. Exposure to high concentrations of Cl- resulted in the increase of ectC expression in log-phase cells with a corresponding accumulation of ectoine at stationary phase. Osmotic stress via MgSO4 exposure did not trigger the same up-regulation of ectC or accumulation of ectoine, indicating the transcriptionally regulated response against osmotic stress was induced by chloride toxicity. These findings have highlighted how the adaptive properties of halo-tolerant organisms in acidic environments are likely to differ and are dependent on the initial stressor.

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

Focal Point of Fanconi Anemia Signaling

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.

The Cross Talk Between p53 and mTOR Pathways in Response to Physiological and Genotoxic Stresses

The tumor suppressor p53 is activated upon multiple cellular stresses, including DNA damage, oncogene activation, ribosomal stress, and hypoxia, to induce cell cycle arrest, apoptosis, and senescence. Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, serves as a central regulator of cell growth, proliferation, and survival by coordinating nutrients, energy, growth factors, and oxygen levels. p53 dysfunction and mTOR pathway hyperactivation are hallmarks of human cancer. The balance between response to stresses or commitment to cell proliferation and survival is governed by various regulatory loops between the p53 and mTOR pathways. In this review, we first briefly introduce the tumor suppressor p53 and then describe the upstream regulators and downstream effectors of the mTOR pathway. Next, we discuss the role of p53 in regulating the mTOR pathway through its transcriptional and non-transcriptional effects. We further describe the complicated role of the mTOR pathway in modulating p53 activity. Finally, we discuss the current knowledge and future perspectives on the coordinated regulation of the p53 and mTOR pathways.

Discovery proteomics defines androgen-regulated glycoprotein networks in prostate cancer cells, as well as putative biomarkers of prostatic diseases

Supraphysiologic androgen (SPA) inhibits cell proliferation in prostate cancer (PCa) cells by transcriptional repression of DNA replication and cell-cycle genes. In this study, quantitative glycoprotein profiling identified androgen-regulated glycoprotein networks associated with SPA-mediated inhibition of PCa cell proliferation, and androgen-regulated glycoproteins in clinical prostate tissues. SPA-regulated glycoprotein networks were enriched for translation factors and ribosomal proteins, proteins that are known to be O-GlcNAcylated in response to various cellular stresses. Thus, androgen-regulated glycoproteins are likely to be targeted for O-GlcNAcylation. Comparative analysis of glycosylated proteins in PCa cells and clinical prostate tissue identified androgen-regulated glycoproteins that are differentially expressed prostate tissues at various stages of cancer. Notably, the enzyme ectonucleoside triphosphate diphosphohydrolase 5 was found to be an androgen-regulated glycoprotein in PCa cells, with higher expression in cancerous versus non-cancerous prostate tissue. Our glycoproteomics study provides an experimental framework for characterizing androgen-regulated proteins and glycoprotein networks, toward better understanding how this subproteome leads to physiologic and supraphysiologic proliferation responses in PCa cells, and their potential use as druggable biomarkers of dysregulated AR-dependent signaling in PCa cells.

Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3

The autophagy-lysosome pathway is a major protein degradation pathway stimulated by multiple cellular stresses, including nutrient or growth factor deprivation, hypoxia, misfolded proteins, damaged organelles, and intracellular pathogens. Recent studies have revealed that transcription factor EB (TFEB) and transcription factor E3 (TFE3) play a pivotal role in the biogenesis and functions of autophagosome and lysosome. Here we report that three translation inhibitors (cycloheximide, lactimidomycin, and rocaglamide A) can facilitate the nuclear translocation of TFEB/TFE3 via dephosphorylation and 14-3-3 dissociation. In addition, the inhibitor-mediated TFEB/TFE3 nuclear translocation significantly increases the transcriptional expression of their downstream genes involved in the biogenesis and function of autophagosome and lysosome. Furthermore, we demonstrated that translation inhibition increased autophagosome biogenesis but impaired the degradative autolysosome formation because of lysosomal dysfunction. These results highlight the previously unrecognized function of the translation inhibitors as activators of TFEB/TFE3, suggesting a novel biological role of translation inhibition in autophagy regulation.

A Different Facet of p53 Function: Regulation of Immunity and Inflammation During Tumor Development

As a key transcription factor, the evolutionarily conserved tumor suppressor p53 (encoded by TP53) plays a central role in response to various cellular stresses. A variety of biological processes are regulated by p53 such as cell cycle arrest, apoptosis, senescence and metabolism. Besides these well-known roles of p53, accumulating evidence show that p53 also regulates innate immune and adaptive immune responses. p53 influences the innate immune system by secreted factors that modulate macrophage function to suppress tumourigenesis. Dysfunction of p53 in cancer affects the activity and recruitment of T and myeloid cells, resulting in immune evasion. p53 can also activate key regulators in immune signaling pathways which support or impede tumor development. Hence, it seems that the tumor suppressor p53 exerts its tumor suppressive effect to a considerable extent by modulating the immune response. In this review, we concisely discuss the emerging connections between p53 and immune responses, and their impact on tumor progression. Understanding the role of p53 in regulation of immunity will help to developing more effective anti-tumor immunotherapies for patients with TP53 mutation or depletion.

Region-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans

Epigenetic alterations occur as organisms age, and lead to chromatin deterioration, loss of transcriptional silencing and genomic instability. Dysregulation of the epigenome has been associated with increased susceptibility to age-related disorders. In this study, we aimed to characterize the age-dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. We focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 in C. elegans. We observed region-specific gain and loss of both histone marks, but the changes are more evident for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most statistically significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in developing worms, which we termed “aging-specific repressive regions” (ASRRs). These ASRRs preferentially occur in genic regions that are marked by high levels of H3K9me2 and H3K36me2 in larval stages. Maintenance of high H3K9me2 levels in these regions have been shown to correlate with a longer lifespan. Next, we examined whether the changes in repressive histone marks lead to de-silencing of repetitive DNA elements, as reported for several other organisms. We observed increased expression of active repetitive DNA elements but not global re-activation of silent repeats in old worms, likely due to the distributed nature of repetitive elements in the C. elegans genome. Intriguingly, CELE45, a putative short interspersed nuclear element (SINE), was greatly overexpressed at old age and upon heat stress. SINEs have been suggested to regulate transcription in response to various cellular stresses in mammals. It is likely that CELE45 RNAs also play roles in stress response and aging in C. elegans. Taken together, our study revealed significant and specific age-dependent changes in repressive histone modifications and repetitive elements, providing important insights into aging biology.

Progress and challenges in understanding the regulation and function of p53 dynamics

The dynamics of p53 expression provide a mechanism to increase differentiation between cellular stresses and specificity in appropriate responses. Here, we review recent advances in our understanding of the molecular mechanisms regulating p53 dynamics and the functions of the dynamics in the regulation of p53-dependent cell stress responses. We also compare dynamic encoding in the p53 system with that found in other important cell signaling systems, many of which can interact with the p53 network. Finally, we highlight some of the current challenges in understanding dynamic cell signaling within a larger cellular network context.