[Aryl-hydrocarbon receptor as a potential target for anticancer therapy]. / Aril-gidrokarbonovyi retseptor kak potentsial'naia mishen' dlia protivorakovoi terapii.

Aryl-hydrocarbon receptor (Aryl Hydrocarbon Receptor, AHR) is a ligand-dependent transcription factor, whose functions are related to xenobiotic detoxification, response to inflammation, and maintenance of tissue homeostasis. Recent investigations suggest that AHR also plays an important role in the processes of carcinogenesis. Increased expression of AHR is observed in several types of tumors and tumor cell lines. In addition, it turned out that the composition of pharmaceutical drugs used in oncotherapy includes some ligands AHR. These facts allow us to consider an aryl-hydrocarbon receptor as a potential target for anticancer therapy, especially for the treatment of severe cancers whose treatment options are very limited or do not exist at all. In this review the examples of AHR ligands' effect on tumor cell cultures and on model mice lines with AHR-dependent response are discussed.

[Overlapping genes and antisense transcription in eukaryotes].

Numerous studies showed that overlapping genes are fairly common elements of genome organization, not only in viruses and prokaryotes but also in eukaryotes. At the same time, the regulatory mechanisms of overlapping gene expression, as well as the functional relevance of antisense transcription, are still relatively unknown. This review describes the history of the discovery of regulatory antisense RNAs, the types of gene overlap, and the putative mechanisms of their functioning. In conclusion, the critical views of different authors on the problem of detecting overlapping genes and an evaluation of the level of antisense transcription are presented.

[Influence of hairpin RNA, specific to the gene lawc, on expression of overlapping genes of the lawc/Trf2 complex in D. melanogaster].

We used a genetic system of the gene complex leg-arista-wing complex/TBP related factor 2 (lawc/Trf2) as a suitable model for in vivo study of operational characteristics of divergent overlapping genes. We established lines of transgenic fruit flies carrying constructs capable of expressing hairpin RNA directed at post-transcriptional suppression of the mRNA gene lawc by way of RNA-interference. The attempt to artificially suppress lawc-transcripts caused a rise in the level of expression of the gene lawc by several times. It is shown that change in the concentration of lawc-transcripts can affect the concentration of Trf2 transcripts. Possible mechanisms of regulation of expression of the overlapping genes studied are discussed.

[D4 family genes in vertebrates: genomic organization and expression].

A family of closely related genes, named the d4 family, has been previously identified in mammals. It comprises three genes encoding structurally related proteins. The hallmark of the family is d4 domain--a double-paired finger motifthat consists of two tandemly arranged PHD finger domains. These genes are expressed in various tissues and at various developmental stages. Two of those, neuro-d4 and cer-d4, are strictly neurospecific and their expression is developmentally regulated. Another gene, ubi-d4/Requiem is ubiquitously expressed in all embryonic and adult tissues at the same levels. d4 family genes are evolutionary conserved. Human, mouse, rat, and chicken d4 genes have been cloned. The only d4-like gene was found in the genome of nematode C. elegans. The sole member of d4 family was identified also in the genome of D. melanogaster. However, d4 genes are not believed to be present in the genomes of prokaryotes and yeast. This review describes genomic organization and expression ofd4family genes in different organisms.

[Effect of mutations in lawc/Trf2 gene on development of chromocenter and chromosome disjunction in Drosophila melanogaster].

In Drosophila, one of the genes of the lawc/Trf2 (leg-arista-wing complex/TBP-related factor 2) complex encodes an alternative basic transcription factor homologous to the TRF2 protein in vertebrates and human and belongs to a conservative Tbp (TATA box-binding protein) gene family. In the present study, reasons for the high frequency of chromosome nondisjunction were studied among descendants of mutants from 18 lines with a decreased expression of the TRF2 protein. It was determined that the suppression of the TRF2 expression violates the development of a compact chromocenter and the correct approach of homologous chromosomes (in germinative and somatic cells). The possibility of the participation of TRF2 in the evolutionary genetically programmed process of sex-ratio violation, which is typical of a number of animal species, is discussed.

[Recovery of genomic regions affecting lawc/Trf2 expression during Drosophila melanogaster development].

Leg-arista-wing complex (lawc) mutations affect the expression of D. melanogaster proteins homologous to a human basic transcription factor, TBP (TATA-box binding protein) Related Factor 2 (TRF2), specifically involved in development. The paper for the first time reports the application of genetic screens for various genomic regions to recover genetic interactions between the lawc/Trf2 gene and other genes and genetic loci by using Deficiency Kit lines with small deletions in total providing maximal coverage of the genome. The deletion mapping allowed us to recover 26 genomic regions that, when deleted, are lethal or modify the mutant phenotype due to a decreased TRF2 expression level. These deletions could be useful in identifying both novel TRF2 targets and its positive and negative regulators. There is evidence that TRF2 can be a component of high molecular DNA Replication-related Element Factor (DREF)- and Nucleosome Remodeling Factor (NURF)-containing complexes. The present study for the first time reports new genetic interactions of lawc/Trf2 with genes that encode basic and specific transcription factors. In most cases, if mutated, those genes caused developmental defects or death of progeny. However, in the case of the e(y) 1 gene, coding for the Taf9 transcription factor, only the male reproductive system is impaired when the lawc/Trf2 phenotype is associated with a e(y)l gene mutation. Mutant lawc(p1)e(y)1(u1) males become infertile due to primary spermatocyte maturation arrest and impaired premeiotic chromosome condensation in germ cells.

[Gene expression modulation is an evolutionary resource of adaptive alterations in the morphogenesis of insect limbs].

Hypomorphic mutations have been investigated of the genes spineless (ss), Distal-less (Dll), leg-arista-wing complex/TBP-related factor 2(lawc/Trf2), CG5017, and hsp 70 in order to explore the effects of their expression level on the formation of distal structures of antenna and legs of Drosophila melanogaster. We demonstrated the effect of the CG5017, hsp 70, Dll, and lawc gene transcription level on phenotypic manifestation of the ss gene mutation and the involvement of these genes into morphogenesis regulation of Drosophila melanogaster limbs. The total decrease in the level of the CG5017, hsp 70, Dll, and laws gene expression level was shown to promote a loss of the segmented pattern of distal structures of legs and antennae and a reversion of Drosophila limb morphogenesis to the evolutionarily earlier progenitors of insects. A hypothesis is proposed considering limb morphogenesis of insects as an evolutionary ancient process of formation of amorphous-crystal chitin structures with catalytically modifying participation of gene expression products.

[Interaction of the ss and CG5017 genes in the regulation of morphogensis of limbs in Drosophila melanogaster].

The influence of the P-element built into the area of the CG5017 gene on the mutation of the spineless (ss) gene was studied. It was shown that the insertion of the P-element decreased the level of transcription of CG5017 approximately twofold. Modulation of the level of transcription of the CG5017 gene helped demonstrate, for the first time, its influence on the phenotypic manifestation of the mutation of the ss gene, which shows their interaction in the process of regulation of morphogenesis of limbs in Drosophila melanogaster.

[Morphogenetic movement of cells in embryogenesis of Drosophila melanogaster: mechanism and genetic control].

Morphogenetic movement of cells is of significant importance in embryogenesis. It is necessary to identify the final position and configuration of the embryoTs tissues and share the positional information in differentiation. The healing of tissular injuries happens in the adult organism due to the cell layers' movement, and the directed macrophages migration to the nidus of infection assists the neutralization of inflammatory processes. Owing to the good level of knowledge, the fruit fly D. melanogaster is a perfect model object for the study of morphogenetic events in embryogenesis in connection with the cells movement. The description of Drosophila embryogenesis, mechanisms of ventral furrow formation, elongation of the germ band, and its contraction accompanied by dorsal closure was given. During these processes the movement of epithelial cells and the entire epithelial strata happens. The information about the genetic regulation of morphogenetic movement of D. melanogaster taking into consideration the scale of evolutionary conservatism of the cascades of the main signal, which control these processes in vertebrates, is presented.

[Source of asymmetry in ontogeny: early polarization of the germline cyst and oocyte in Drosophila].

One or more body axes are already formed in the egg in many vertebrates and invertebrates. In Drosophila, the anteroposterior and dorsoventral axes are determined during oogenesis owing to the asymmetric localization of the bicoid, oskar, and gurken mRNAs in the oocyte (prospective egg). The localization of these transcripts depends on the polarized organization of the oocyte cytoskeleton and, consequently, the oocyte polarity. Initial asymmetry, leading to the oocyte polarity, is established in early ontogeny, during oocyte determination. The review considers the steps of early polarization and oocyte differentiation in Drosophila, the genetic control of these processes, and the findings that suggest an early oocyte polarity for vertebrates.

[Overexpression of a novel gene toothrin in Drosophila].

A newly found locus of the Drosophila melanogaster genome, named toothrin (tth) has been used to study the role of the conserved domain 2/3 of genes from the d4 family. In contrast to the 2/3 domain of all vertebrates studied (including humans), which is always accompanied by the d4 domain, the tth gene contains the sequence encoding the 2/3 domain but lacks that encoding the d4 domain. The tth gene overexpression has been studied using the two-component system UAS-GAL4. It has been demonstrated that the tth overexpression at the third-instar larval (prepupal) stage decreases survival rate, simultaneously causing a substantial deceleration of development in Drosophila. It is known that the change of developmental stages in Drosophila is controlled by the rates of the expression of ecdysteroid and juvenile hormones (JHs). It is supposed that the overexpression of the tth gene causes either a shift in the ecdysterone-to-JH ratio (through a decreased JH decay rate or a delayed initiation of ecdysone synthesis) or a deceleration of the release of ecdysterones synthesized.

[Use of a genetic system of the chimeric protein P-Ph in the repression of gene transcription of the leg-arista-wing complex in Drosophila]. / Ispol'zovanie geneticheskoi sistemy khimernogo belka P-Ph dlia repressii transkriptsii gena leg-arista-wing complex u Drozofily.

Preliminary analysis of the leg-arista-wing complex (lawc) gene region in the corresponding mutants revealed P element insertion in the transcribed region of this locus. To demonstrate the main role of P element insertion in the complex pleiotropic phenotypic manifestation of the lawc gene, a system using P-Ph chimeric protein and based on the P-mediated repression of the lawc in vivo transcription was applied. As a result, extreme lawc-mutant phenotypes were obtained and examined. The P-Ph-mediated decrease of the level of the lawc gene transcription was also demonstrated.

Cerd4, third member of the d4 gene family: expression and organization of genomic locus.

Two members of the d4 family of presumptive transcription modulators, neuro-d4 (Neud4) and ubi-d4/Requiem (Req), have been characterized previously. We cloned and characterized the third member of this gene family, cer-d4 (Cerd4), from chicken and mouse cDNA libraries. The expression patterns of Cerd4 gene in both species are similar and more restricted than expression patterns of other two d4 genes. The main sites of Cerd4 expression are retina and cerebellum, where multiple transcripts could be detected. Two major types of Cerd4 proteins are a full-length isoform possessing all domains characteristic to the d4 family and truncated XZ isoform without C-terminal tandem of PHD fingers. The developmental kinetics of expression of these isoforms is different. The intron/exon structure of human Cerd4 gene is similar to that of neuro-d4 and ubi-d4/Requiem genes, but most introns of Cerd4 gene are much larger than the corresponding introns of the other two genes.

[A novel trans-regulatory locus in Drosophila]. / Novyi trans-reguliatornyi lokus drozofily.

A new trans-regulatory gene, leg-arista-wing complex (lawc), was earlier identified in a system of prolonged genetic instability induced by transpositions of structurally different mobile genetic elements, the P element and MDG Stalker. Mutations of this gene alter expression of many loci, including the achaete and scute proneural genes and the cut locus coding for a homeobox-containing protein. A product of lawc is involved in regulating expression of white. This role is played in cooperation with the product of Zeste which provides for a contact between the white promoter and enhancer. A possible role of the new locus in organogenesis, neurogenesis, and embryonic development is discussed on the basis of experimental findings.

[Study of the olfactory response in the Drosophila homeotic mutant leg-aristae-wing complex gene]. / Issledovanie ol'faktornoi chuvstvitel'nosti u gomeozisnykh mutantov gena leg-aristae-wing complex u drozofily.

Antennae are known to be olfactory organs in Drosophila. The leg-aristae-wing complex (lawc) mutation causes a homeotic transformation of the arista (the fifth element of antenna) into tarsal elements. To test how the homeotic transformation of the arista into the tarsus can affect behavior, we studied the olfactory response in the lawc mutants. The data were carefully processed by statistical methods. In spite of a low penetrance of the trait of arista transformation, the mutant flies were found to be approximately half as perceptible to attractant odors than the wild-type flies.

[Taste sensitivity in homeotic mutants of the drosophila leg-arista-wing complex]. / Issledovanie vkuxovoi chuvsvitel'nosti u gomeozisnykh mutantov gena leg-arista-wing complex drozofily.

It is well established that taste chemoreceptors in Drosophila are located on the tarsi of the first leg pair. In order to investigate the influence of the novel homeotic arista-tarsus transformation on behavior, an analysis of taste perception in the lawc-mutants, characterized by the transformation of the arista into tarsus elements, was carried out. The data were subjected to thorough statistical treatment. It was shown that elements of an additional leg that appeared as a result of homeotic transformation of the arista were sensitive to gustatory stimuli. Analysis of the innervation of the homeotic organs by means of cobalt staining of afferent projections showed that the afferents starting from the homeotic leg reached the thoracic ganglion.

[Genomic organization of the murine neuro-d4 gene]. / Genomnaia organizatsiia gena neuro-d4 myshi.

As the first step toward obtaining the null mutation or knock out of the neuro-d4 gene, we isolated phages containing fragments of the gene from a mouse genomic library. The nucleotide sequence of a region of the gene more than 10 kb in size was determined.