Showing papers in "Critical Reviews in Eukaryotic Gene Expression in 2008"

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. The toxicity of the potent AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin is almost exclusively mediated through this receptor. However, the key alterations in gene expression that mediate toxicity are poorly understood. It has been established through characterization of AhR-null mice that the AhR has a required physiological function, yet how endogenous mediators regulate this orphan receptor remains to be established. A picture as to how the AhR/ARNT heterodimer actually mediates gene transcription is starting to emerge. The AhR/ARNT complex can alter transcription both by binding to its cognate response element and through tethering to other transcription factors. In addition, many of the coregulatory proteins necessary for AhR-mediated transcription have been identified. Cross talk between the estrogen receptor and the AhR at the promoter of target genes appears to be an important mode of regulation. Inflammatory signaling pathways and the AhR also appear to be another important site of cross talk at the level of transcription. A major focus of this review is to highlight experimental efforts to characterize nonclassical mechanisms of AhR-mediated modulation of gene transcription.

Matrix Metalloproteinase Control of Capillary Morphogenesis

Abstract: Matrix metalloproteinases (MMPs) play crucial roles in a variety of normal (e.g. blood vessel formation, bone development) and pathophysiological (e.g. wound healing, cancer) processes. This is not only due to their ability to degrade the surrounding extracellular matrix (ECM), but also because MMPs function to reveal cryptic matrix binding sites, release matrix-bound growth factors inherent to these processes, and activate a variety of cell surface molecules. The process of blood vessel formation, in particular, is regulated by what is widely classified as the angiogenic switch: a mixture of both pro- and anti-angiogenic factors that function to counteract each other unless the stimuli from one side exceeds the other to disrupt the quiescent state. While it was initially thought that MMPs were strictly pro-angiogenic, new functions for this proteolytic family such as mediating vascular regression and generating matrix fragments with antiangiogenic capacities have been discovered in the last decade. These findings cast MMPs as multi-faceted pro- and anti-angiogenic effectors. The purpose of this review is to introduce the reader to the general structure and characterization of the MMP family and to discuss the temporal and spatial regulation of their gene expression and enzymatic activity in the following crucial steps associated with angiogenesis: degradation of the vascular basement membrane; proliferation and invasion of endothelial cells within the subjacent ECM, organization into immature tubules; maturation of these nascent vessels; and the pruning and regression of the vascular network.

Isoform diversity, regulation, and functional adaptation of troponin and calponin.

Abstract: Actin-activated myosin II motor function powers muscle contraction and nonmuscle cell motility. The actin-myosin-derived contractility has evolved with a great diversity in different muscle and cell types. Actin filament-based regulation controls striated muscle contraction and plays a role in modulating smooth muscle contractility and nonmuscle cell motility. This review focuses on the isoform diversity and functional adaptations of troponin in striated muscle and calponin in smooth muscle and nonmuscle cells. The gene regulation, alternative RNA splicing, and posttranslational modifications of troponin I and troponin T are summarized, together with recent progress in calponin studies. The biologic significance of the structural and functional diversity and regulation of troponin and calponin is discussed for roles in normal contractility and diseases.

Expression and activity of aryl hydrocarbon receptors in development and cancer.

Abstract: Although the aryl hydrocarbon receptor (AhR) has been known as the mediator of the toxicity of particular xenobiotics such as the dioxins, the normal role of this transcription factor in a number of biological processes is just beginning to be recognized. Knowledge of AhR-targeted genes and signaling pathways indicates involvement of AhR in fundamental cell-regulatory pathways. Noted defects in the morphology and functions of certain tissues in the absence of AhR point to critical roles for this protein in developmental processes. Together, the data suggest that the AhR has an important function in controlling the balance among processes involved in cell proliferation, death, and differentiation rather than being essential for them. On the other hand, deregulation of these processes is known to contribute to events such as tumor initiation, promotion, and progression that ultimately lead to malignant tumor formation. Epidemiological and experimental animal data, along with a more detailed understanding of how AhR is involved in regulating particular signaling pathways, provide substantial support for an association between abnormal AhR function and cancer. Here we describe the current understanding of how the AhR may function to regulate both normal and cancerous tissue growth and development.

The ROS-NOX connection in cancer and angiogenesis.

Abstract: Initially viewed as dangerous byproducts of aerobic life, reactive oxygen species (ROS) nowadays appear to be essential secondary messengers of many signaling cascades and cellular functions. The establishment of ROS as important signaling molecules has been confirmed by the existence of specialized ROS producing complexes expressed in nonphagocytic cells, the NADPH oxidase complex (NOX). Because of the diversity of their proteic targets (besides lipids and DNA), ROS have multiple and sometimes contradictory functions. In the present review, we focus on several different signaling pathways influenced by ROS and NOX in tumorigenesis, focusing on proliferation and angiogenesis. We review the ROS targets regulating proliferation, including cellular signaling (phosphatases, AP1, and nuclear factor-kappa B [NF-kappaB]) and cell cycle targets (CDC25, cyclin D, and forkhead proteins), and the role of NOX during proliferation. Finally, we review the direct and indirect involvement of ROS and NOX in (tumor) angiogenesis through the regulation of different biologic systems such as vascular endothelial growth factor, angiotensin II, hypoxia-inducible factor, AP1, and inflammation.

Regulation of chondrocytic gene expression by biomechanical signals.

Abstract: Cartilage is a mechanosensitive tissue, which means that it can perceive and respond to biomechanical signals. Despite the known importance of biomechanical signals in the etiopathogenesis of arthritic diseases and their effectiveness in joint restoration, little is understood about their actions at the cellular level. Recent molecular approaches have revealed that specific biomechanical stimuli and cell interactions generate intracellular signals that are powerful inducers or suppressors of proinflammatory and reparative genes in chondrocytes. Biomechanical signals are perceived by cartilage in magnitude-, frequency-, and time-dependent manners. Static and dynamic biomechanical forces of high magnitudes induce proinflammatory genes and inhibit matrix synthesis. Contrarily, dynamic biomechanical signals of low/physiologic magnitudes are potent antiinflammatory signals that inhibit interleukin-1beta (IL-1beta)-induced proinflammatory gene transcription and abrogate IL-1beta/tumor necrosis factor-alpha-induced inhibition of matrix synthesis. Recent studies have identified nuclear factor-kB (NF-kB) transcription factors as key regulators of biomechanical signal-mediated proinflammatory and antiinflammatory actions. These signals intercept multiple steps in the NF-kappaB signaling cascade to regulate cytokine gene expression. Taken together, these findings provide insight into how biomechanical signals regulate inflammatory and reparative gene transcription, underscoring their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.

Progesterone Receptor Isoform Functions in Normal Breast Development and Breast Cancer

Abstract: Progesterone acting through two isoforms of the progesterone receptor (PR), PRA and PRB, regulates proliferation and differentiation in the normal mammary gland in mouse, rat and human. Progesterone and PR have also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is on recent advances in understanding the role of the PR isoform specific functions in the normal breast and in breast cancer. Also discussed is information obtained from rodent studies and their relevance to our understanding of the role of progestins in breast cancer etiology.

Sex differences in muscle-derived stem cells and skeletal muscle.

Abstract: Sex is well known to influence life expectancy and disposition to disease. Stem and progenitor cells are believed to persist throughout life, and they contribute to the repair and healthy maintenance of tissue; consequently, sex-related differences demonstrated by stem cells may provide insight to sex-related differences in aging, disease, and healing. However, cell sex is an often overlooked variable in stem cell biology.

Transcriptional control of the differentiation program of interfollicular epidermal keratinocytes.

Abstract: Mammalian epidermis is a stratified squamous epithelium that serves as a protective barrier against external harmful elements. The development of the epidermis is a highly regulated process that begins by the commitment of a single layer of multipotent ectodermal cells to a keratinocyte cell fate. This is followed by stratification and a subsequent elaborate program of differentiation leading to the generation of a multilayered epidermis and patterned cutaneous appendages such as the hair follicles and sebaceous glands. The stratified epidermis occupying the space between skin appendages is referred to as the interfollicular epidermis (IFE) and is the focus of this review. Within the IFE, keratinocytes in the innermost basal layer are mitotically active. Upon specific cues, these cells undergo cell cycle arrest and execute a terminal differentiation program as they progress through spinous, granular, and cornified layers. This program operates continually throughout the life of an organism; dead cells sloughed off from the skin surface are replenished by basal cells moving outward in a highly synchronized fashion. Not surprisingly, at the heart of the control process is a dedicated group of transcription factors that ensure the integrity of the keratinocyte differentiation program by regulating gene expression in a temporally and spatially coordinated manner. Here we review the transcription factors that play important roles in the development and maintenance of IFE as evidenced by biochemical and genetic studies.

Vitamin d control of gene expression: temporal and spatial parameters for organization of the regulatory machinery

Abstract: Vitamin D is a principal modulator of skeletal gene expression, thus necessitating an understanding of interfaces between the activity of this steroid hormone and regulatory cascades that are functionally linked to the regulation of skeletal genes. Physiologic responsiveness requires combinatorial control, whereas co-regulatory proteins determine the specificity of biologic responsiveness to physiologic cues. It is becoming increasingly evident that regulatory complexes containing the vitamin D receptor are dynamic rather than static. Temporal and spatial modifications in the composition of these complexes provide a mechanism for integrating regulatory signals to support positive or negative control through synergism and antagonism. Compartmentalization of components of vitamin D control in nuclear microenvironments supports the integration of regulatory activities, perhaps by establishing thresholds for protein activity in time frames that are consistent with the execution of regulatory signaling.

The epigenetics of adult (somatic) stem cells.

Abstract: While genetic studies have provided a wealth of information about health and disease, there is a growing awareness that individual characteristics are also determined by factors other than genetic sequences. These “epigenetic” changes broadly encompass the influence of the environment on gene regulation and expression and in a more narrow sense, describe the mechanisms controlling DNA methylation, histone modification and genetic imprinting. In this review, we focus on the epigenetic mechanisms that regulate adult (somatic) stem cell differentiation, beginning with the metabolic pathways and factors regulating chromatin structure and DNA methylation and the molecular biological tools that are currently available to study these processes. The role of these epigenetic mechanisms in manipulating adult stem cells is followed by a discussion of the challenges and opportunities facing this emerging field.

The amelogenin "enamel proteins" and cells in the periodontium.

Abstract: This overview will examine the multifunctional nature of a group of proteins known as the amelogenins. These secreted proteins were named in the 1960s because of their expected role during development of dental enamel [Eastoe JE. Adv Fluorine Res. 1965;21:5-17]. As gene expression assays became more sensitive, expression was also noted in tissues not involved with enamel formation leading to hypotheses concerning additional roles for these proteins. In vitro approaches led to the discovery that some of the amelogenins are able to regulate gene expression and to participate in cellular signaling. An extract containing predominately amelogenins has been used clinically in treatment of certain forms of pcriodontal disease with regenerative results noted originally in animal models, but later in human patients as well. Much literature has been devoted to the roles of amelogenins during mineral formation, and therefore this topic will be covered primarily in the Introduction. The goal of this review will be to focus on strategies that have been used to uncover roles of amelogenins related to gene expression and development apart from the roles in enamel mineral, and the possible functions that these proteins could have if delivered to normally nonexpressing tissues for therapeutic approaches.

Determinants of pathologic mineralization.

Abstract: Physiologic mineralization is necessary for the formation of skeletal tissues and for their appropriate functions during adulthood. Mineralization has to be controlled and restricted to specific regions. If the mineralization process occurs in regions that normally do not mineralize, there can be severe consequences (pathologic or ectopic mineralization). Recent findings have indicated that physiologic and pathologic mineralization events are initiated by matrix vesicles, membrane-enclosed particles released from the plasma membranes of mineralization-competent cells. The understanding of how these vesicles are released from the plasma membrane and initiate the mineralization process may provide novel therapeutic strategies to prevent pathologic mineralization. In addition, other regulators (activators and inhibitors) of physiologic mineralization have been identified and characterized, and there is evidence that the same factors also contribute to the regulation of pathologic mineralization. Finally, programmed cell death (apoptosis) may be a contributor to physiologic mineralization and if occurring after tissue injury may induce pathologic mineralization and mineralization-related differentiation events in the injured and surrounding areas. This review describes how the understanding of mechanisms and factors regulating physiologic mineralization can be used to develop new therapeutic strategies to prevent pathologic or ectopic mineralization events.

Clinical relevance of transgenic mouse models for aging research.

Abstract: Studies on transgenic mice have shown them to be useful models for human aging- and age-related diseases. Life span end points in yeast and Caenorhabditis elegans can identify highly conserved genes that promote longevity when their functions are lost and which can readily be manipulated in the mouse. Protein kinase A is an example of a highly conserved gene that has age-delaying effects when specific subunits are suppressed or removed in the mouse, suggesting that loss of function may be a rational pharmacologic target. Gain of function is also an attractive clinical approach because expression levels of some vital genes may decrease in an age-related manner. The antioxidant enzyme catalase can delay aging when the human gene is inserted into mitochondria of mice. Other antioxidant genes are of interest in this system, both individually and in combination with catalase. A challenging aspect is to determine how to deliver catalase, as well as other gene products, into the mitochondria in the clinical setting. A number of new and exciting genes will most likely be investigated as clinical antiaging targets as the result of a forward genetic life span screening approach in invertebrates and a reverse genetic life span approach in the mouse.

Signaling mechanisms controlling taste cell function.

Abstract: Sensory systems have evolved to collect information about the environment. Each system has developed to gather specific data that are pertinent to an organism's needs, and consequently the systems vary in their abilities to detect external stimuli such as light, sound, vibration, magnetic fields, or chemicals. Although not all sensory systems are present in all organisms, all organisms, even those at the single-cell level, have the ability to detect chemicals in the environment. Chemical detection likely evolved out of organisms' needs to detect food sources and avoid potentially harmful compounds. Higher-level organisms developed two sensory systems to detect environmental chemicals: olfaction and taste. Olfaction is used in many behaviors, such as kin recognition and mate selection, whereas taste is used primarily to determine whether potential food items will be ingested or rejected. The sense of taste involves the detection of five taste qualities: bitter, sweet, salty, sour, and umami, which is the detection of amino acids, specifically glutamate. Because the chemical structures of taste qualities are diverse, numerous mechanisms are used by taste cells to detect these stimuli. This review focuses on our current understanding of the signaling mechanisms used by taste cells to transduce stimulus signals.

A close examination of genes within quantitative trait loci of bone mineral density in whole mouse genome.

Abstract: Bone mineral density (BMD) is one of the strongest determinants of osteoporotic fracture risk. Over the last decade, a large number of quantitative trait loci (QTL) that regulate BMD have been identified using the mouse model. In an attempt to examine the relationship between those QTL and gene distribution in the mouse genome, we searched PubMed with keywords bone and QTL for every publication up to January 2007; we obtained a total of 75 QTL of BMD. We next obtained genes within a QTL for measurements of BMD from the Ensembl database. We then evaluated the potential connection of every gene with bone biology with Online Mendelian Inheritance in Man (OMIM) and PubMed by using eight key words: bone mineral density, BMD, bone strength, bone size, osteoporosis, osteoblast, osteoclast, and fracture. We obtained a total of 15,084 genes for 75 BMD QTL covering 1,211,376,097 base pairs of genomic sequence. Although this very large number of genes exists within QTL regions, only 291 were identified as candidate genes according to our bioinformatics search. Importantly, the association between polymorphism of many candidate genes and BMD has been reported in human studies. Thus, updated genome information and resources should provide new insight for gene identification of QTL. Accordingly, the comprehensive search of candidate genes in the genome for known QTL may provide unexpected benefits for QTL studies.

Nuclear trafficking of the G-protein-coupled parathyroid hormone receptor.

Abstract: G-protein-coupled receptors are a family of receptors that signal primarily through heterotrimeric G proteins. However, new evidence has emerged to show that the signaling capabilities of the receptors are beyond those of traditional signaling cascades. One such example is that the parathyroid hormone (PTH) type 1 receptor is found not only at the plasma membrane but also in the nucleus of cells in cell lines and tissues. This review discusses the emerging concepts of nuclear PTH signaling and relates this information to the growing field of nuclear G-protein-coupled receptors. We review recently published studies on the mechanism of PTH nuclear localization, its role in the cell nucleus, and the contrasting roles ligands play in regulating the receptors' nuclear localization. The review also discusses the importance of nuclear G-protein-coupled receptors and future directions for research in this field.

Gene expression in pulmonary fibrosis.

Abstract: Pulmonary fibrosis is a phenotype that results from a variety of conditions and is associated with significant morbidity and mortality. Ongoing research in the field is driven by the need for effective treatments for pulmonary fibrosis. In this review, we highlight mechanisms that regulate gene expression in pulmonary fibrosis at multiple levels. Potential pathogenic mechanisms involve genetic background and transcriptional, posttranscriptional, translational, posttranslational, and epigenetic mechanisms. Pulmonary fibrosis results from abnormal gene expression and regulation that arise from a combination of inherited/acquired genetic alterations and environmental triggers. Collectively, these alterations result in increased expression of extracellular matrix components such as collagen and fibronectin and in the observed fibrosis. Insights gained from mechanisms identified to induce and/or perpetuate fibrosis in the lung will yield new targets for the development of more effective therapies.