Maria Nurminskaya

Bio: Maria Nurminskaya is an academic researcher from University of Maryland, Baltimore. The author has contributed to research in topics: Tissue transglutaminase & Vascular smooth muscle. The author has an hindex of 22, co-authored 44 publications receiving 2072 citations. Previous affiliations of Maria Nurminskaya include Tufts University & University of Maryland, College Park.

Transglutaminase Regulation of Cell Function

Abstract: Transglutaminases (TGs) are multifunctional proteins having enzymatic and scaffolding functions that participate in regulation of cell fate in a wide range of cellular systems and are implicated to have roles in development of disease. This review highlights the mechanism of action of these proteins with respect to their structure, impact on cell differentiation and survival, role in cancer development and progression, and function in signal transduction. We also discuss the mechanisms whereby TG level is controlled and how TGs control downstream targets. The studies described herein begin to clarify the physiological roles of TGs in both normal biology and disease states.

Selective sweep of a newly evolved sperm-specific gene in Drosophila

Abstract: The pattern of genetic variation across the genome of Drosophila melanogaster is consistent with the occurrence of frequent ‘selective sweeps’, in which new favourable mutations become incorporated into the species so quickly that linked alleles can ‘hitchhike’ and also become fixed1 Because of the hitchhiking of linked genes, it is generally difficult to identify the target of any putative selective sweep Here, however, we identify a new gene in D melanogaster that codes for a sperm-specific axonemal dynein subunit The gene has a new testes-specific promoter derived from a protein-coding region in a gene encoding the cell-adhesion protein annexin X (AnnX), and it contains a new protein-coding exon derived from an intron in a gene encoding a cytoplasmic dynein intermediate chain (Cdic) The new transcription unit, designated Sdic (for sperm-specific dynein intermediate chain), has been duplicated about tenfold in a tandem array Consistent with the selective sweep of this gene, the level of genetic polymorphism near Sdic is unusually low The discovery of this gene supports other results that point to the rapid molecular evolution of male reproductive functions2,3,4

Collagen fibrillogenesis in situ: Fibril segments undergo post‐depositional modifications resulting in linear and lateral growth during matrix development

Abstract: Elucidating how collagen fibril growth is regulated is important in determining how tissues are assembled. Fibrils are deposited as segments. The growth of these segments is an important determinant of tissue architecture, sta- bility, and mechanical attributes. Fibril segments were isolated from developing tendons and their structure characterized. The post-depositional changes leading to linear and lateral growth of fibrils also were examined. Segments extracted from 14-day chicken embryo tendons had a mean length of 29 pm. The segments were asymmetric, having a short and a long tapered end. Most of the segments were centrosymmetric with respect to molecular packing. Segments extracted from 12- to 16-day tendons had the same structure, but mean segment length increased incrementally due to the addition of an increasingly large population of longer segments. At 17 days of development there was a precipitous increase in segment length. The morphological data indicate that the increase in length was the result of lateral associ- ations among adjacent segments. Analysis demon- strated that this fibril growth was associated with a significant decrease in fibril associated decorin. Using immunoelectron microscopy, decorin was seen to decrease significantly at 18 days of devel- opment. When decorin content was biochemically determined, a decrease also was observed. Decorin mRNA also decreased relative to fibrillar collagen mRNA during the same period. These data support the hypothesis that a decrease in fibril-associated decorin is necessary for fibril growth associated with tissue maturation. Growth through post-depositional fusion allows for appo- sitional and intercalary growth and would be es- sential for normal development, growth, and repair. 0 1995 Wiley-Liss, Inc.

Cellular functions of tissue transglutaminase.

Abstract: Transglutaminase 2 (TG2 or tissue transglutaminase) is a highly complex multifunctional protein that acts as transglutaminase, GTPase/ATPase, protein disulfide isomerase, and protein kinase. Moreover, TG2 has many well-documented nonenzymatic functions that are based on its noncovalent interactions with multiple cellular proteins. A vast array of biochemical activities of TG2 accounts for its involvement in a variety of cellular processes, including adhesion, migration, growth, survival, apoptosis, differentiation, and extracellular matrix organization. In turn, the impact of TG2 on these processes implicates this protein in various physiological responses and pathological states, contributing to wound healing, inflammation, autoimmunity, neurodegeneration, vascular remodeling, tumor growth and metastasis, and tissue fibrosis. TG2 is ubiquitously expressed and is particularly abundant in endothelial cells, fibroblasts, osteoblasts, monocytes/macrophages, and smooth muscle cells. The protein is localized in multiple cellular compartments, including the nucleus, cytosol, mitochondria, endolysosomes, plasma membrane, and cell surface and extracellular matrix, where Ca(2+), nucleotides, nitric oxide, reactive oxygen species, membrane lipids, and distinct protein-protein interactions in the local microenvironment jointly regulate its activities. In this review, we discuss the complex biochemical activities and molecular interactions of TG2 in the context of diverse subcellular compartments and evaluate its wide ranging and cell type-specific biological functions and their regulation.

Identification and characterization of up-regulated genes during chondrocyte hypertrophy

Abstract: Chondrocyte hypertrophy involves de novo acquisition and/or increased expression of certain gene products including, among others, type X collagen, alkaline phosphatase, and matrix metalloproteinases. To analyze further the genetic program associated with chondrocyte hypertrophy, we have employed a modification of the polymerase chain reaction-mediated subtractive hybridization method of Wang and Brown (Wang and Brown [1991] Proc. Natl. Acad. Sci 88:11505). Cultures of hypertrophic tibial chondrocytes and nonhypertrophic sternal cells were used for poly A+ RNA isolation. Among 50 individual cDNA fragments isolated for up-regulated hypertrophic genes, 18 were tentatively identified by their similarities to entries in the GenBank database, whereas the other 32 showed no significant similarity. The identified genes included translational and transcriptional regulatory factors, ribosomal proteins, the enzymes transglutaminase and glycogen phosphorylase, type X collagen (highly specific for hypertrophic cartilage matrix), gelsolin, and the carbohydrate-binding protein galectin. Two of these, transglutaminase and galectin, were cloned and were further characterized. The chondrocyte transglutaminase revealed previously in hypertrophic cartilage by immunochemical methods appears to be the chicken equivalent of mammalian factor XIIIa (showing 75% overall protein similarity). The chicken chondrocyte galectin is a variant of mammalian galectin-3. Galectins are known to bind to components found in hypertrophic cartilage, and factor XIIIa is known to crosslink some of the same components, possibly modifying them for calcification and/or removal. © 1996 Wiley-Liss, Inc.

Matrix Proteoglycans: From Molecular Design to Cellular Function

Abstract: The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.

Collagen fibril formation

Abstract: Collagen is most abundant in animal tissues as very long fibrils with a characteristic axial periodic structure. The fibrils provide the major biomechanical scaffold for cell attachment and anchorage of macromolecules, allowing the shape and form of tissues to be defined and maintained. How the fibrils are formed from their monomeric precursors is the primary concern of this review. Collagen fibril formation is basically a self-assembly process (i.e. one which is to a large extent determined by the intrinsic properties of the collagen molecules themselves) but it is also sensitive to cell-mediated regulation, particularly in young or healing tissues. Recent attention has been focused on "early fibrils' or "fibril segments' of approximately 10 microns in length which appear to be intermediates in the formation of mature fibrils that can grow to be hundreds of micrometers in length. Data from several laboratories indicate that these early fibrils can be unipolar (with all molecules pointing in the same direction) or bipolar (in which the orientation of collagen molecules reverses at a single location along the fibril). The occurrence of such early fibrils has major implications for tissue morphogenesis and repair. In this article we review the current understanding of the origin of unipolar and bipolar fibrils, and how mature fibrils are assembled from early fibrils. We include preliminary evidence from invertebrates which suggests that the principles for bipolar fibril assembly were established at least 500 million years ago.

Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility

Abstract: Decorin is a member of the expanding group of widely distributed small leucine-rich proteoglycans that are expected to play important functions in tissue assembly. We report that mice harboring a targeted disruption of the decorin gene are viable but have fragile skin with markedly reduced tensile strength. Ultrastructural analysis revealed abnormal collagen morphology in skin and tendon, with coarser and irregular fiber outlines. Quantitative scanning transmission EM of individual collagen fibrils showed abrupt increases and decreases in mass along their axes, thereby accounting for the irregular outlines and size variability observed in cross-sections. The data indicate uncontrolled lateral fusion of collagen fibrils in the decorindeficient mice and provide an explanation for the reduced tensile strength of the skin. These findings demonstrate a fundamental role for decorin in regulating collagen fiber formation in vivo.

The genic view of the process of speciation

Abstract: The unit of adaptation is usually thought to be a gene or set of interacting genes, rather than the whole genome, and this may be true of species differentiation. Defining species on the basis of reproductive isolation (RI), on the other hand, is a concept best applied to the entire genome. The biological species concept (BSC; Mayr, 1963) stresses the isolation aspect of speciation on the basis of two fundamental genetic assumptions ‐ the number of loci underlying species differentiation is large and the whole genome behaves as a cohesive, or coadapted genetic unit. Under these tenets, the exchange of any part of the genomes between diverging groups is thought to destroy their integrity. Hence, the maintenance of each species’ genome cohesiveness by isolating mechanisms has become the central concept of species. In contrast, the Darwinian view of speciation is about differential adaptation to different natural or sexual environments. RI is viewed as an important by product of differential adaptation and complete RI across the whole genome need not be considered as the most central criterion of speciation. The emphasis on natural and sexual selection thus makes the Darwinian view compatible with the modern genic concept of evolution. Genetic and molecular analyses of speciation in the last decade have yielded surprisingly strong support for the neo-Darwinian view of extensive genetic differentiation and epistasis during speciation. However, the extent falls short of what BSC requires in order to achieve whole-genome ‘cohesiveness’. Empirical observations suggest that the gene is the unit of species differentiation. Significantly, the genetic architecture underlying RI, the patterns of species hybridization and the molecular signature of speciation genes all appear to support the view that RI is one of the manifestations of differential adaptation, as Darwin (1859, Chap. 8) suggested. The nature of this adaptation may be as much the result of sexual selection as natural selection. In the light of studies since its early days, BSC may now need a major revision by shifting the emphasis from isolation at the level of whole genome to differential adaptation at the genic level. With this revision, BSC would in fact be close to Darwin’s original concept of speciation.

The Evolution of Transcriptional Regulation in Eukaryotes

Abstract: Gene expression is central to the genotype-phenotype relationship in all organisms, and it is an important component of the genetic basis for evolutionary change in diverse aspects of phenotype. However, the evolution of transcriptional regulation remains understudied and poorly understood. Here we review the evolutionary dynamics of promoter, or cis-regulatory, sequences and the evolutionary mechanisms that shape them. Existing evidence indicates that populations harbor extensive genetic variation in promoter sequences, that a substantial fraction of this variation has consequences for both biochemical and organismal phenotype, and that some of this functional variation is sorted by selection. As with protein-coding sequences, rates and patterns of promoter sequence evolution differ considerably among loci and among clades for reasons that are not well understood. Studying the evolution of transcriptional regulation poses empirical and conceptual challenges beyond those typically encountered in analyses of coding sequence evolution: promoter organization is much less regular than that of coding sequences, and sequences required for the transcription of each locus reside at multiple other loci in the genome. Because of the strong context-dependence of transcriptional regulation, sequence inspection alone provides limited information about promoter function. Understanding the functional consequences of sequence differences among promoters generally requires biochemical and in vivo functional assays. Despite these challenges, important insights have already been gained into the evolution of transcriptional regulation, and the pace of discovery is accelerating.