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Major (CD9, CD63, CD81) and others (CD82, CD151, Tspan8) tetraspanins are widely represented in exosomes, where they interact with various proteins and form functional tetraspanin complexes. Tetraspanin complexes include proteases. Tetraspanin-associated exosomal proteases (ADAM proteases, MMPs, EMMPRIN) play an important role in the processes of cell motility, migration, invasion and formation of metastases. Also, a significant contribution to tumor progression is made by proteases that are not associated with tetraspanins. They destabilize intercellular contacts, promote migration and invasion of tumor cells, participate in the regulation of the expression IGF-I, VEGF and transcription factors activation/deactivation. The role of other proteases of exosomes in the processes of tumor progression is being clarified.

Septins belong to a family of conserved GTP-binding proteins found in majority of eukaryotic species except for higher plants. Septins form nonpolar complexes that further polymerize into filaments and associate with cell membranes, thus comprising newly acknowledged cytoskeletal system. Septins participate in a variety of cell processes and contribute to various pathophysiological states, including tumorigenesis and neurodegeneration. Here, we review the structural and functional properties of septins and the regulation of their dynamics with special emphasis on the role of septin filaments as a cytoskeletal system and its interaction with actin and microtubule cytoskeletons. We also discuss how septins compartmentalize the cell by forming local protein-anchoring scaffolds and by providing barriers for the lateral diffusion of the membrane proteins.

Furin belongs to serine intracellular Ca2+-dependent endopeptidases of the subtilisin family, also known as proprotein convertase (PC). Human furin is synthesized as zymogen with a molecular weight of 104 kDà, which is then activated by autocatalytic in two stages. This process can occur when zymogen migrates from the endoplasmic reticulum to the Golgi apparatus, where a large part of furin is accumulated. The molecular weigh t of the active furin is 98 kDà. Furin relates to enzymes with a narrow substrate specificity: it hydrolyzes peptide bonds at the site of paired basic amino acids and furin activity exhibits in a wide pH range 5-8. Its main biological function is activation of the functionally important protein precursors. It is accompanied by the launch of a cascade of reactions, which lead to appearance of biologically active molecules involved in realization of specific biological functions both in normal and in some patologicheskih processes. Furin substrates are biologically important proteins such as enzymes, hormones, growth factors and differentiation, receptors, adhesion proteins, proteins of blood plasma. Furin plays an important role in the development of processes such as proliferation, invasion, cell migration, survival, maintenance of homeostasis, embryogenesis, as well as the development of a number of pathologies, including cardiovascular, oncologic and neurodegenerative diseases. Furin and furin-like proprotein convertases participate as key factors in the realization of the regulatory functions of proteolytic enzymes, the value of which is currently being evaluated as most important in comparison with the degradative function of proteases.

The aim of the study was to investigate the activity of arginase of mixed saliva with the subsequent application of the results obtained in clinical laboratory diagnostics. Arginine metabolic parameters were studied in particular arginase activ- ity, concentration of nitric oxide, urea and uric acid. There was found a three-fold increase of arginase activity and a four- fold reduction of nitric oxide in mixed saliva of patients on the background of cancer. There was established inverse rela- tionship between arginase activity and nitric oxide as well as between the concentration of urea and nitrogen oxides. Basic possibility of differential diagnosis of benign and malignant neoplastic disease was showed .using chemometric methods. Imbalance of arginase activity and nitric oxide in the saliva of cancer patients could be an important diagnostic and prog- nostic criterion.

Tyrosyl phosphorylation participates in various pathological and physiological processes, which are regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The Src homology-2 domain containing phosphatase SHP2 (encoded by PTPN11) is an important phosphatase, which was found to be implicated in the regulation of genetic disease, development, metabolic, neurological, muscle, skeletal disease and cancer. Germline mutations in PTPN11 cause the Noonan Syndrome, LEOPARD syndrome and metachondromatosis. Somatic PTPN11 mutations occur in hematologic malignancies and in solid tumors. SHP2 is also an important component in oncogenic signaling pathways. It may play different roles in different stages and positions of human cancers. Whether SHP2 is an oncogene or cancer suppressor gene remains to be elucidated. Elucidation of the regulatory mechanisms of SHP2 in human disease will provide new insights into disease and new targets for therapy. Here, we summarized the structural basis and recent research progression on SHP2 in various human disease, including genetic and cancer diseases.

Activity of the proteasome, polyfunctional enzymatic complex, is known to undergo changes during cancer development. This phenomenon is, probably, caused by the changes in subunit composition of proteasomes. In present work, we studied chymotrypsin-like activity of proteasomes, subunit composition and their association in breast cancer, head and neck squamous cell carcinoma, endometrial cancer, renal cancer, bladder cancer, stomach cancer and colorectal cancer. The increase of proteasome activity was revealed in most cancer tissues compared with adjacent tissues except for the renal cell carcinoma. Changes in proteasome activity in cancer tissues compared with correspondent normal tissues were accompanied by modification of its subunit composition. High proteasome activity was observed in combination with an increased expression of immune subunits and/or proteasome activator PA28, associated with activity of 20S proteasome. In breast cancer, head and neck squamous cell carcinoma, bladder cancer, stomach cancer and colorectal cancer we additionally found higher expression of Rpt6 subunit of 26S proteasome. Correlations between chymotrypsin like proteasome activity and subunit expressions were found in human cancer tissues. In summary, we suggest that proteasome ac- tivation and changes in its subunit composition plays an important role in cancer pathogenesis.

The review of the literature about the results of the study of the role of 4a/b VNTR-polymorphism of eNOS in pathophysiology of various states of the body. It is shown that the data are ambiguous and sometimes contradictory. The study of the contribution of candidate genes to the implementation of multifactorial diseases can increase the accuracy of prediction of the set of risk factors, early diagnosis facilitate and sufficient therapy of multifactorial diseases.

Ubiquitin-dependent proteasomal degradation is one of the major pathways of non-lysosomal protein degradation in the cell. The ubiquitination process involves several enzymatic reactions and includes the following enzymes: E1--activating, E2--conjugating, and the third--E3--ligating enzymes. E3 ligases determine the specificity of ubiquitination reaction, i. e. what target protein will be subjected to the covalent modification by ubiquitins. The p53b tumor suppressor protein is one of the most intensively studied over the past several decades. Regulation of its activity is a complex and multi-level process that involves many factors. Ubiquitination is one of the major post-translational modifications of p53, and plays a fundamental role in the control of p53 function, its amount, activity and subcellular localization. This review is focused on p53-specific E3 ubiquitin ligases that are potential targets for cancer therapy using small molecule inhibitors.

Review is devoted to detailed consideration of the functioning in normal and immortal cells of one of the main chromosomal regions, telomeres, being dynamic nucleoprotein structures that cap the ends of eukaryotic chromosomes, protecting them from degradation and end-to-end fusion. The role of telomeres in maintenance of genome stability and cell division was also analyzed. Telomere function depends on many interrelated parameters such as telomerase activity, status of the telomere safety complex shelterin and telomere associated proteins (factors of replication, recombination, and reparation of DNA breaks, and so on). We have focused on mechanisms of telomere length control in normal and immortal cells as well as in cells containing active telomerase and cells wherein it is absent. We have analyzed the features attributed to alternative telomere lengthening, namely in view of recently discovered additional mechanism of telomere shortening by trimming of t-cycles. We have viewed a possibility of expression in normal mammalian cells of both telomerase dependent and recombinational ways of telomere length control and the role of shelterin proteins in choice of the one of them as the dominant way. The role oftelomeres in spatial organization of nucleus, in mitosis and meiosis has been also considered. Diversity of telomere organization in mammalians including unusual telomeres in Iberian shrews has been discussed.

Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19 +/- 0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0 +/- 0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line.

Purine nucleoside phosphorylase (PNP) catalyzes reversible phosphorolysis of purine deoxy- and ribonucleosides with formation (d)Rib-1-P and corresponding bases. PNP plays a leading role in the cell metabolism of nucleosides and nucleotides, as well as in maintaining the immune status of an organism. The major aim of the majority of studies on the PNP is the detection of highly effective inhibitors of this enzyme, derivatives ofpurine nucleosides used in medicine as immunosuppressors, which are essential for creating selective T-cell immunodeficiency in a human body for organ and tissue transplantation. The present work is devoted to the study of the effects of some synthetic derivatives of purine nucleosides on activity of highly purified PNP from rabbit spleen and also from human healthy and tumor tissues of lung and kidneys. Purine nucleoside analogues modified at various positions of both the heterocyclic base and carbohydrate residues have been investigated. Several compounds, including 8-mercapto-acyclovir, 8-bromo-9-(3,4-hydroxy-butyl)guanine, which demonstrated potent PNP inhibition, could be offered for subsequent study as immunosuppressors during organ and tissue transplantation.

Transglutaminasc (protein-glutamine gamma-glutamyltransferase, EC 2.3.2.13, TG) catalyzes reactions of the acyl transfer, which introduce the epsilon-(gamma-glutamyl)lysine bonds between proteins to create polymers of high mol. mass. Properties of the TG enzyme are described. Its structure is considered: there are characterized items of the TG life cycle and stability, its biological (physiological) role, and significance in pathology and medicine as well as obtaining of the purified enzyme preparations and their use. There are compared TG from different sources: of animal and microbial origin. Mechanism of catalysis of microbial TG is discussed. There are presented characteristics of isoenzymes from different biological sources.

Summarised data about polymorphism of xenobiotic metabolism enzyme system (XMES) have been presented. Metabolic molecular mechanisms and the role of genetic polymorphism in metabolic transformation of different xenobiotics are reviewed. Significance of X-transport proteins and nuclear receptors in regulation of XMES-activity are discussed. Possible connection of XMES polymorphism with the development of cancer was examined. Experimental modeling of different levels of epoxide syntase and epoxide hydratase activites has revealed their connection with cancer development. Physiological factors should be considered when evaluation of risk extent for cancer development is carried out.

Mutations in the genes of corrective 3' --> 5'-exonucleases as well as in DNA polymerases lead to decrease in DNA biosynthesis accuracy all over genome. This is accompanied by the increase in mutagenesis and carcinogenesis probabilities. In this work, the activities of 3' --> 5'-exonucleases and DNA polymerases were studied in the extracts from normal and cancer cells of rodents and humans, and we are the first to measure their integral ratios. As example, in cultivated dermal fibroblasts of an adult human, the value of the ratio of activities of 3' --> 5'-exonucleases to DNA polymerase activity (3'-exo/pol) surpassed several folds the such a value for HeLa cells. Similar picture was observed during the comparison of normal fibroblasts of rat embryos and transformed fibroblasts of Chinese hamster A238. Experiments with cell-free extracts of some organs from healthy rats of various ages have shown that normal proliferating cells demonstrate higher 3' --> 5'-exonuclease activity and higher values of 3'-exo/pol that quiescent cells. Comparison of these data suggests a violation of the function of corrective 3' --> 5'-exonucleases in abnormally growing cancer cells.

The novel views on fundamental role of Na+,K(+)-ATPase in regulation of the polarized morphology of the epithelial cells, enzyme involvement in signal transduction, assembly of intermolecular signaling complexes have been reviewed. The modern state of researches are considered in detail, including: sorting specificity in polarized cells, Na+,K(+)-ATPase involvement in epithelial cell interactions, enzyme arrangement in combined structural and functional ensemble with adhesion and cytoskeleton proteins, their coordinated exp ression. The mechanisms of the Na+,K(+)-ATPase association with its molecular partners and the role of specific domains, motives and binding sites are analysed. The available data, including own researches indicate the Na+,K(+)-ATPase involvement in certain pathologies that develop with aberration of polarized epithelial phenotype, malignant growth in particular.

Matrix metalloproteinases and their inhibitors play an essential role in invasion and dissemination of malignant tumors. The study of expression of MMP and their inhibitors in solid and blood cancer may appear a key study giving assessment of antitumor response.

Flap endonuclease-1 (FEN1) is a structure specific endonuclease. The natural substrates of FEN1 are 5'-flap structures formed by three DNA chains one of them has unannealed flapped 5'-end (flap). Flap structures are the intermediates of different processes of DNA metabolism, such as DNA recombination, Okazaki fragment maturation during replication of lagging strand, as well as strand displacement DNA synthesis in base excision repair. FEN1 also possesses 5'-exonuclease activity and newly discovered gap endonuclease activity. FEN1 is known to interact physically and functionally with a number of DNA replication and repair proteins such as the proliferating cell nuclear antigen, helicase/nuclease Dna2, WRN and BLM proteins, replication protein A, apurinic/apyrimidinic endonuclease 1, DNA polymerase beta, poly(ADP-riboso) polymerase 1, high mobility group protein 1, integrase of human immunodeficiency virus, transcription coactivator p300, chromatin proteins, cyclin-dependent kinases (Cdk1, Cdk2, Cyclin A). FEN1 activity is significant for maintaining the integrity of repeat sequences in genome. Recent data suppose the correlation between the abnormality of hFEN1 activity and arising/progression of neurodegenerative and cancer diseases. FEN1 has the dramatic effect on cell growth and development thereby attracting the interest to this enzyme.

The literature and our experimantal data about the role of carboxypeptidases in carcinogenesis have been reviewed. Activity of all groups of the enzymes increases under development of different tumors. In some cases it is possible to suppose existence of protective role of these enzymes which is directed to inhibition of tumor development.

The data about deoxyribonuclease activity in blood of healthy donors and patients with malignant and autoimmune diseases are described. Methodological aspects of the analysis of DNase activity and factors which interfere with DNase activity in blood are discussed.

Poly(ADP-ribose) polymerases (PARP) is enzyme family repairing single or double DNA strand breaks induced by different alkylating agents, ionizing- or UV-irradiation as well as by oxidative stress. Poly(ADP-ribose) polymerase-1 (PARP-1) is the most studied enzyme involved in a number of pathways including DNA replication and repair, recombination, gene transcription, cell proliferation and death. A positive correlation between the PARP-activity and the life span of different mammalians has been detected. PARP inhibition in vitro with inhibitors of PARP activity (3-aminobenzamide, nicotinamide, picolinamide e.t.c.) in cells from wild type or PARP-1(-/-) mice was followed by high genomic instability (i.e. aneuploidy, gene amplifications and deletions, micronuclei formation, sister chromatic exchange, cell ploidy and centrosome number increase) and increased sensitivity to mutagens. Life span reduction, latency period of spontaneous tumors development shortening and the increase in susceptibility to carcinogens have been observed in PARP-knockout mice. Treatment with PARP inhibitors stimulated chemical and radiation carcinogenesis in animals. The PARP-1(-/-) mice being additionally disrupted in WRN, p53, DNA-PKcs or Ku80 genes the promotion of spontaneous carcinogenesis was observed as compared with a single gene-disrupted mice. Available data suggest a significant role of PARP in maintenance of genomic stability, preventing of aging and carcinogenesis.

A current state of researches on mechanisms of ion homeostasis regulation in the specific conditions of the uncontrolled malignant tumor growth (mainly in carcinomas) concerning the contribution of Na+,K+-ATPase, plasma membrane and sarco(endo)plasmic reticulum Ca2+-ATPases has been reviewed. Particular attention has been focused on the molecular and biochemical links providing the redistribution of the transporting ATPases isozyme pattern for the regulatory requirements of the cell signaling pathways at stable proliferation and viability in malignancy.

Ceruloplasmin (CP) is a copper containing oxidase of human plasma alpha 2-globulin fraction. The review summarizes literature data on biological role of CP under normal conditions and during development of malignant tumor. This protein may be involved both into antitumor deference and also into metastasizing process. Although CP has already been employed into intensive therapy of oncologic patients all mechanisms underlying its biological activity remain to be clarified.

We studied the role of nitric oxide synthase during tumor growth in oncovirus-induced tumor mutants of Drosophila melanogaster. The lines with different capacity for malignancy differed reliably in the level of enzymatic activity. It was shown using specific inhibitors of neuronal and inducible isoforms that the neuronal isoform was not involved in tumor formation, while the inducible one appears to play an important role in tumor growth inhibition. This isoform was identified with the help of immunoblotting and monoclonal antibodies against inducible nitric oxide synthase.

This review is devoted to the role of low molecular weight antioxidants and antioxidant enzymes in cancerogenesis. The data on accumulation of lipid-soluble and water-soluble antioxidants in a number of malignant human and experimental tumors especially in the renal cell carcinoma tissues are analyzed. A possibility is discussed concerning the pro- and anticarcinogenic effects of the abundant tumor content of antioxidants. Implication of antioxidants in tumor resistance to chemotherapeutic drugs and ionizing radiation is discussed.

One of the new directions in study of malignant tumor pathogenesis is telomerase theory. Investigations in the culture of human cells have shown that telomerase activation can lead to tumor development. Prospective investigations of telomerase could be able to supplement the data about tumor pathomorphology and will permit to conduct monitoring on patients with malignant tumors by studying telomerase in fractionated cells from different body tissues and biological media. Telomerase inhibitors are possible drugs for antitumoral therapy. It is supposed that the abovementioned agents will decrease telomerase activity of proliferating tumoral cells that will cause destabilization of their genome, stopping of proliferation and death of tumoral clone.

Plasma-membrane-enriched particles isolated from the tissues of malignant tumors of different sites are shown to accumulate ATP under the influence of polypeptide growth factors and cytokines whose receptors have a tyrosine kinase activity. Polypeptide growth factors, such as EGF, FGF, NGF, TNF, insulin, and the cytokine IL-2, were studied on the accumulation of adenosine-5'-triphosphate (ATP) by the preparations of plasma-membrane-enriched particles isolated from the target tissues of human malignant tumors. The tumor (transformed) cell plasma membranes of the lung, bowel, stomach, pancreas, as well as the cells of neurinoma and a retroperitoneal extra-organ malignant tumor (leiomyosarcoma) are demonstrated to be able to synthesize ATP from inorganic phosphate and ADP under aerobic conditions human with the participation of the cyanide-insensitive proton phoric NADH-bound transversely oriented chain. Signal-stimulated accumulation of plasma membranous ATP was found to increase in the tissues in malignant transformation as compared to that in normal tissues. Experiments using selective inhibitors of tyrosine kinases (tyrphostin-25, quercetin) indicated the involvement of plasma membranous signal-transducing ATP in the activation of receptor tyrosine kinase growth factors.

The paper presents the results of study on polymorfisms of xenobiotic biotransformation enzymes (CYP1A1, glutathione S-transferase MI and N-acetyltransferase 2) and p53 tumor suppressor protein in patients with lung, stomach and intestine cancer. The frequency of CYP1A1-Val allele in all studied cancer groups was 3 to 5 times higher than in healthy control group. The carriers of homozygous glutathione S-transferase M1 gene deletion and slow acetylator phenotype were also of higher lung cancer risk. The substantial increase in slow acetylator phenotype frequency was shown also in the group of intestine cancer patients. The p53 Arg/Pro polymorphism study revealed the elevated frequency of Arg allele in lung and stomach cancer groups. The risk of lung cancer for the carriers of susceptible alleles depended on the age and smoking status of the patients. The results testify to a high possibility of studied polymorphic genes to be the markers of susceptibility to oncopathologies.

Lipid peroxidation (LP) occurring in pediatric cancer patients receiving polychemotherapy has been investigated. Plasma level of malonic dialdehyde in children with retinoblastoma (Rtb) was found to drop while it remained unchanged in patients with acute lymphoblastic leukemia (ALL). The treatment caused different changes in the red cell catalase levels in said groups: the enzyme concentration increased in the Rtb patients in the course of therapy and decreased in the ALL group. A slight decline in alpha-tocopherol and retinol levels the Rtb group was matched by a relevant rise in blood-plasma in the ALL group. To adjust LP regulation and improve resistance, antioxidants should be given to pediatric cancer patients suffering peroxidation-related stress.

Putative mechanisms by which proteinases and their inhibitors participate in tumour invasion and possible involvement of proteinase inhibitors in tumour growth regulation are considered. The significance of proteinases and their inhibitors for diagnosis of cancer is evaluated.

The authors analyze the correlation between the frequency of detection of alpha-naphthylacetate esterase in peripheral blood lymphocytes and T helper/inductor ratio determined by immunological methods from CD-4 MCAB expression. The results indicate that the counts of esterase-positive lymphocytes cytochemically detected by alpha-naphthylacetate esterase activity reliably correlated with T helper counts assessed by immunoperoxidase method with Technicon H-1 flow analyzer.

Liver monooxygenase (MO) activity was evaluated in 31 children with oncological diseases. The enzyme activity was assessed by measuring the saliva half life of the test drug antipyrine. It was shown that MO activity is reduced in hepatitis, metastatic lesions of the liver, after long-term chemotherapy, combined treatment or progress of disease. Considerable individual variations in MO activity were observed even in cases of comparable pathologies during examinations. It is suggested that therapeutic response in patients with low MO liver levels could be optimized by appropriately stimulating said enzyme system prior to chemotherapy.