Ubiquitination of signaling receptors triggers their endocytosis to restrict the extent of cell signaling. Type 1 interferon (IFN1) eliminates its receptor from cell surface via stimulating the ubiquitination of its IFNAR1 chain. While it was suggested that this ubiquitination aids IFNAR1 internalization via relieving a steric hindrance of a linear motif within IFNAR1 from the endocytic machinery, the mechanisms involved remain poorly understood. Here we describe a specific role for two disparate ubiquitin acceptor sites within this receptor. These sites, Lys501 and Lys525 / 526, exhibit a preference for polyubiquitination via either Lys63- or Lys48‑linked chains (K63‑Ub and K48‑Ub, respectively). Whereas the SCFβTrcp E3 ubiquitin ligase controls either type of ubiquitination-dependent IFNAR1 endocytosis, the specificity of these processes is determined by two different E2 ubiquitin conjugating enzymes, Ubc13 and Cdc34. These enzymes can be directly used by SCFβTrcp E3 ubiquitin ligase to generate either K63‑Ub or K48‑Ub in vitro. Ubc13 is involved in IFNAR1 endocytosis driven by the K63‑Ub modification of Lys501, whereas the K48‑Ub-specific Cdc34 affects receptor endocytosis via ubiquitin conjugation that occurs on
Lys525 / 526. Both types of linkages combine to maximize IFNAR1 endocytosis otherwise suppressed by unfavorable conformation dependent on the presence of a conserved Pro470 within the intracellular domain of IFNAR1. We propose a model where alternate utilization of both E2s to assemble diverse polyubiquitin linkages cooperates to achieve IFNAR1 intracellular domain conformations and spatial arrangements that favor a maximal rate of receptor endocytosis.

Importance of molecular genetics-based essays in clinical oncology is now unquestionable due to the fact that all oncological diseases and their progression are based on cascading accumulation of genetic aberrations involving more than 20 different genes. Essentially new capacities of clinical oncology are uncovered with the help of modern molecular biology methods that allow to determine structural and functional changes of genes and their products. This review examines approaches to improve criteria for creating diagnostic essays, evaluation of treatment efficiency and molecular factors of clinical course. In order to determine relevant markers, special consideration should be given to the research of signal transduction pathways involving key genes responsible for tumor growth and their partners. The correct formation of patient’s groups and selection of samples is very important. It is emphasized that integrated clinical programs should combine traditional methods of diagnostics and treatment with modern molecular testing and bioinformatics methods.

5–10 % of breast cancer cases are hereditary, 30 % of them are caused by BRCA1 and BRCA2 mutations (breast / ovarian cancer syndrome). Average cumulative risks of breast and ovarian cancer in BRCA1 mutation carriers run up to 87 % and 44 %, correspondingly. The risk for contralateral breast cancer is also high: after 25 years, 62.9 % of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer develop contralateral breast cancer. The role of single nucleotide polymorphisms in BRCA1 and BRCA2 genes modifying breast and gynaecological cancer risks is actively studied. Genetic testing is performed as a part of genetic counselling. The main inclusion criteria are multiple affected family members with breast / ovarian cancer, breast cancer at young age (under 35–50 years), ovarian cancer at any age, male breast cancer, morphological features of breast cancer (triple-negative, medullar tumors), ethnicity (Jewish ancestry). High-risk individuals carrying BRCA mutations undergo specific surveillance, chemoprophylaxis and surgery protocols. Prophylactic bilateral mastectomy reduces breast cancer risk by 90–94 %.

Melanoma remains the most deadly form of malignant skin disease with high risk of metastases. Metastatic melanoma is prognostic highly unfavorable and resistant to traditional chemotherapy and biologic treatment. There is a great progress in understanding of the molecular mechanisms underlying melanoma initiation and progression. The external (ultraviolet irradiation) and internal (genetic) factors are involved in melanoma genesis. 5–14 % of melanoma cases occur in familial context due to genetic predisposition risk factors. Among them rare germinal mutations in the cell cycle genes regulators CDKN2A and CDK4 and in the master gene of melanocyte homeostasis MITF, as well as single nucleotide polymorphisms of several low-penetrated genes, namely MC1R, have been identified. The main cell signaling pathways 
and oncogene driver mutations are involved in melanoma pathogenesis. RAS / RAF / MEK / ERK cascade is hyperactivated in 75 % of cutaneous melanoma cases. Activation of PI3K / AKT / mTOR signaling pathway is important for melanoma progression. Recent studies revealed that melanomas are genetically and phenotypically heterogeneous tumors. Spectrum of chromosomal alterations and activating mutations corresponding to tumor molecular portraits varies in melanomas of different location. Most of cutaneous melanomas contain BRAF (50 %) or NRAS (20 %) mutations, and NRAS mutations occur on chronically sun-exposed skin. Activating KIT mutations have been reported in approximately 20–30 % of certain subtypes of melanoma, including acral and mucosal, and melanoma that develop on photodamaged skin. Cutaneous metastatic melanoma derive from preexisting nevi in 25 % of cases, molecular mechanisms of nevi malignization are discussed. Deepsequencing approaches of melanoma samples of different melanoma types highlighted new melanoma driver genes, that are damaged due to tumorigenic effects of ultraviolet: PPP6C, RAC1, SNX31, TACC1 and STK19. The progress in melanoma studies allow to receive the positive results in melanoma treatment in particularly with targeted therapy. The molecular targets and future perspectives for targeted therapy of metastatic skin melanoma are discussed.

Kidney cancer (renal cell carcinoma) is one of the major problems of modern urological oncology. In Russia renal cell carcinoma accounts
for 4.3 % of all cancers. The global incidence of renal cell carcinoma has increased over the past two decades. Worldwide renal cell carcinoma accounts for 3.6 % of all cancers and is 10th frequent malignancy. For some malignancies, for instance tumours of prostate, there are markers known that allowed improved early diagnostics. Kidney cancer, however, remains to be hard to diagnose and to treat, since the symptoms can be detected on advanced stages of the disease. In Russia 75.4 % of renal cell carcinoma cases detected at the stage of local and locally advanced disease. Though there are various target drugs on the market aimed to treat this disease, the results of renal cell carcinoma treatment did not reach any substantial success. Most of existing target drugs for kidney cancer treatment include inhibitors of a single signaling
pathway regulated by VHL1, which expression is lost in the vast majority of renal-cell carcinomas. Till now existing drugs did not reach sufficient efficacy. Therefore, it is highly important to search for new signaling pathways, regulating such cellular processes as proliferation, migration and apoptosis. Further, prognostic markers and therapy targets identified so far are not sufficient and poorly specific. Therefore identification and validation of new markers, and especially new specific targets for the treatment of kindey oncopathologies is highly important and timely task.

In this review the role of hypoxia and glycolysis in tumor expansion is described. Experimental results demonstrate that glycolysis functions in tumor cells are not restrict only energy supply. Glycolysis stimulates the activity of transcription factor HIF-1α. Assemble of HIF1α and protein ARNT stimulates expression of numerous genes. Among others there are genes coding glycolysis proteins, telomerase, P-glycoproteins, antiapoptotic proteins belonging to Bcl-2 family, inhibitor of pyruvate dehydrogenase – pyruvate dehydrogenase kinase and others. The inhibition of mitochondia respiratory chain by inhibition of pyruvate dehydrogenase stimulates accumulation in cell pyruvate. Lactate dehydrogenase transforms pyruvate in lactate. Accumulation of lactate in tumour cells activates monocarboxylate transporter. Lactate and proton transport into intercellular region. Due to it is observed pH drop in tumour tissue. The low level of pH in tumour tissue stimulates metalloprotease activity. Metalloprotease activity disrupt the intercellular matrix. In tumour region with low pH level the enhancement of invasion is observed. The restoration of normal pH level in tumor tissue inhibits invasion and metastasis. It is possible to conclude that hypoxia is a physiological tumour state that support and promote tumor process. It is some informaton about antitumour effects of inhibitors of different stages of glycolysis. Inhibitors of hexokinase – 2‑deoxy-D-glucose and lonidamine inhibit adenosine triphosphate formation as well as
P-glycoprotein activity. For some tumour types these compounds are toxic. The inhibition of P-glycoprotein activity stimulates antineoplastic activity of cytostatics. Dichloroacetate inhibits pyruvate dehydrogenase kinase activity. Inclusion of respiratory chain in situation when oxygen level is low stimulates reactive oxygen species formation. Reactive oxygen species are able stimulate apoptosis. It is shown that dichloroacetate is very toxic for some forms of tumour. It is discussed the possibility to use the different inhibitors of the different glycolytic stages as anticancer compounds

Objectives. To develop the Amniocar nutrient medium that contains fetal calf serum (FCS) and growth factors cocktail for mass cultivation of human fibroblasts. To study proliferative activity of the medium on cultures of HUVEC cells of mesenchymal origin and mesenchymal stromal cells, as well as on cell culture of human amniotic fluid.

Materials and methods. Determination of the rate of accumulation of the cellular mass and cell morphology in the course of cultivation of cells of various histogenesis in the Amniocar medium and nutrient medium that contains 10 % of FCS.

Results. It has been demonstrated that the Amniocar medium is prevalent as compared to the standard DMEM medium with 10 % of FCS by 2 to 5 times for cultivation of skin fibroblasts, HUVEC, and mesenchymal stem cells. The Amniocar medium increased the quantity of endothelial cells that enter mitosis and maintained the culture of HUVEC cells with prolonged passaging in vitro. Clonal cultivation of human amniotic fluid cells in the Amniocar medium secured development of colonies of both fibroblast and epithelial type.

Conclusions. Proliferative Amniocar medium is efficient for mass cultivation of various cells of mesenchymal origin and can be used for diagnostic purposes in medical genetics, oncology, etc.