Human Papillomaviruses (HPVs) are double-stranded DNA viruses, that infect epithelial cells and are etiologically involved in the development of human cancer. Today, over 200 types of human papillomaviruses are known. They are divided into low-risk and high-risk HPVs depending on their potential to induce carcinogenesis, driven by two major viral oncoproteins, E6 and E7. By interacting with cellular partners, these proteins are involved in interdependent viral and cell cycles in stratified differentiating epithelium, and concomitantly induce epigenetic changes in infected cells and those undergoing malignant transformation. E6 and E7 oncoproteins interact with and/or modulate expression of many proteins involved in epigenetic regulation, including DNA methyltransferases, histone-modifying enzymes and subunits of chromatin remodeling complexes, thereby influencing host cell transcription program. Furthermore, HPV oncoproteins modulate expression of cellular micro RNAs. Most of these epigenetic actions in a complex dynamic interplay participate in the maintenance of persistent infection, cell transformation, and development of invasive cancer by a considerable deregulation of tumor suppressor and oncogenes. In this study, we have undertaken to discuss a number of studies concerning epigenetic regulations in HPV-dependent cells and to focus on those that have biological relevance to cancer progression.

Insulin-like growth factor (IGF) system stimulates growth, proliferation, and regulates differentiation of cells in a tissue-specific manner. It is composed of two insulin-like growth factors (IGF-1 and IGF-2), six insulin-like growth factor-binding proteins (IGFBPs), and two insulin-like growth factor receptors (IGF-1R and IGF-2R). IGF actions take place mostly through the activation of the plasma membrane-bound IGF-Rs by the circulating ligands (IGFs) released from the IGFBPs that stabilize their levels in the serum. This review focuses on the IGF-1 part of the system. The IGF-1 gene, which is expressed mainly in the liver as well as in other tissues, comprises six alternatively spliced exons that code for three protein isoforms (pro-IGF-1A, pro-IGF-1B, and pro-IGF-1C), which are processed to mature IGF-1 and E-peptides. The IGF-1R undergoes autophosphorylation, resulting in a signaling cascade involving numerous cytoplasmic proteins such as AKT and MAPKs, which regulate the expression of target genes. However, a more complex picture of the axis has recently emerged with all its components being translocated to the nuclear compartment. IGF-1R takes part in the regulation of gene expression by forming transcription complexes, modifying the activity of chromatin remodeling proteins, and participating in DNA damage tolerance mechanisms. Four IGFBPs contain a nuclear localization signal (NLS), which targets them to the nucleus, where they regulate gene expression (IGFBP-2, IGFBP-3, IGFBP-5, IGFBP-6) and DNA damage repair (IGFBP-3 and IGFBP-6). Last but not least, the IGF-1B isoform has been reported to be localized in the nuclear compartment. However, no specific molecular actions have been assigned to the nuclear pro-IGF-1B or its derivative EB peptide. Therefore, further studies are needed to shed light on their nuclear activity. These recently uncovered nuclear actions of different components of the IGF-1 axis are relevant in cancer cell biology and are discussed in this review.

Many attempts have been made to define nature of viruses and to uncover their origin. Our aim within this work was to show that there are different perceptions of viruses and many concepts to explain their emergence: the virus-first concept (also called co-evolution), the escape and the reduction theories. Moreover, a relatively new concept of polyphyletic virus origin called “three RNA cells, three DNA viruses” proposed by Forterre is described herein. In this paper, not only is each thesis supported by a body of evidence but also counter-argued in the light of various findings to give more insightful considerations to the readers. As the origin of viruses and that of living cells are most probably interdependent, we decided to reveal ideas concerning nature of cellular last universal common ancestor (LUCA). Furthermore, we discuss monophyletic ancestry of cellular domains and their relationships at the molecular level of membrane lipids and replication strategies of these three types of cells. In this review, we also present the emergence of DNA viruses requiring an evolutionary transition from RNA to DNA and recently discovered giant DNA viruses possibly involved in eukaryogenesis. In the course of evolution viruses emerged many times. They have always played a key role through horizontal gene transfer in evolutionary events and in formation of the tree of life or netlike routes of evolution providing a great deal of genetic diversity. In our opinion, future findings are crucial to better understand past relations between viruses and cells and the origin of both.

Efficient delivery of heterologous molecules for treatment of cells is a great challenge in modern medicine and pharmacology. Cell penetrating peptides (CPPs) may improve efficient delivery of a wide range of macromolecular cargos including plasmid DNA, small interfering RNA, drugs, nanoparticulate pharmaceutical carriers and anticancer drugs. In this paper, we present history of CPPs' discovery with a special attention drawn to sequences of viral origin. We also describe different CPP families with regard to their physicochemical properties and numerous mechanisms of CPP cell uptake by direct penetration and endocytotic pathways. A detailed description is focused on formation of carrier-cargo complexes, which are needed for practical use of CPP in medicine and biotechnology. Examples of successful application of CPPs in treatment of human diseases are also presented, including decreased tumor growth and induction of cancer cell death. Finally, we review modern design approaches to novel CPPs and prediction of their activity. To sum up, the current review presents a thorough and up-to-date knowledge about CPPs and may be a valuable source of information for researchers in pharmacology designing new therapeutic agents.

IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor.

Insulin‐like growth factors (IGFs) are essential for local skeletal muscle growth and organismal physiology, but these actions are entwined with glucose homeostasis through convergence with insulin signaling. The objective of this work was to determine whether the effects of IGF‐I on growth and metabolism could be separated. We generated muscle‐specific IGF‐I‐deficient (MID) mice that afford inducible deletion of Igf1 at any age. After Igf1 deletion at birth or in young adult mice, evaluations of muscle physiology and glucose homeostasis were performed up to 16 wk of age. MID mice generated at birth had lower muscle and circulating IGF‐I, decreased muscle and body mass, and impaired muscle force production. Eight‐wk‐old male MID had heightened insulin levels with trends of elevated fasting glucose. This phenotype progressed to impaired glucose handling and increased fat deposition without significant muscle mass loss at 16 wk of age. The same phenotype emerged in 16‐wk‐old MID mice induced at 12 wk of age, compounded with heightened muscle fatigability and exercise intolerance. We assert that muscle IGF‐I independently modulates anabolism and metabolism in an age‐dependent manner, thus positioning muscle IGF‐I maintenance to be critical for both muscle growth and metabolic homeostasis.—Vassilakos, G., Lei, H., Yang, Y., Puglise, J., Matheny, M., Durzynska, J., Ozery, M., Bennett, K., Spradlin, R., Bonanno, H., Park, S., Ahima, R. S., Barton, E. R. Deletion of muscle IGF‐I transiently impairs growth and progressively disrupts glucose homeostasis in male mice. FASEB J. 33, 181–194 (2019). www.fasebj.org