Band 3, Heft 4

The Pat1 protein family has been the subject of several recent extensive investigations of diverse model systems ranging from yeast, flies and worms to man, using a variety of experimental approaches. Although some contradictions remain, the emerging consensus view is that these RNA-binding proteins act in mRNA decay by physically linking deadenylation with decapping and by regulating gene expression as translational repressors. These multiple functions are present in the single invertebrate Pat1 proteins, whereas, in vertebrates, one Pat1 variant represses translation in early development, while a somatic version synthesised in embrogenesis and in adults acts in mRNA decay. At steady state, Pat1 proteins are found enriched in cytoplasmic P(rocessing)-bodies, and related mRNP complexes and granules. Evidence recently obtained from mammalian tissue culture cells shows that Pat1 shuttles in and out of the nucleus, where it localises to nuclear speckles, PML bodies and nucleolar caps, which suggests RNA-related nuclear functions. Less well understood, Pat1 proteins may play additional roles in miRNA silencing and/or biogenesis, as well in the regulation of viral gene expression. Due to the relatively low level of sequence conservation between Pat1 proteins from different species and lacking any discernable motifs, determining their functional domains has proved difficult, as is obtaining a simple unified view of the location of the binding sites of their interacting proteins in all examined species. Questions that remain to be addressed include the following: 1) What are their roles in the nucleus? 2) What is the link, if one exists, between their cytoplasmic and nuclear roles? 3) Do they have specific mRNA targets? 4) Which signalling pathways regulate their P-body localisation in mammalian cells, which may affect quiescent cell survival?

Like many other small GTPases, Ran functions in eukaryotic cells as a molecular switch that cycles between GTP- and GDP-bound forms. Through the proper modulation of the GTP/GDP cycle, Ran functions with a number of Ran-binding proteins to control a broad array of fundamental cellular functions, including nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope and nuclear pore complex formation. Recent studies have revealed that ‘Ran and Ran binding proteins’ are involved in a variety of functions involving cell fate determination, including cell death, cell proliferation, cell differentiation, and malignant transformation. In this review, we discuss recent progress on the functional link between the Ran system and tumorigenesis, which give clues to the molecular understanding of cancer biology.

Overexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2–6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

Embryogenesis and morphogenesis are characterized by complex cell rearrangements and movements which require appropriate interactions of cells with the surrounding extracellular matrix (ECM) by means of specific membrane receptors. Interest in the identification and purification of ECM components, as well as in conducting functional studies of them, including their ligands and other molecules involved in cell-matrix adhesion, has intensified in recent years, increasing our knowledge of developmental machinery. Cellular movements play an important role during the epithelial-mesenchymal transition (EMT) events, which are key processes in normal embryogenesis as well as in pathological conditions, such as fibrotic diseases and cancer. Thus, to more fully understand mechanisms underlying the EMT process, and for better knowledge of the embryonic defects related to this process, it would be useful to study the substrates on which EMT cells move during embryo development. This review focuses on a few different embryonic systems, taking into account the cell migration that occurs during EMT and highlighting, in particular, studies describing the direct involvement of ECM molecules.

Hyperosmotic stress is an often overlooked process that potentially contributes to a number of human diseases. Whereas renal hyperosmolarity is a well-studied phenomenon, recent research provides evidence that many non-renal tissues routinely experience hyperosmotic stress that may contribute significantly to disease initiation and progression. Moreover, a growing body of evidence implicates hyperosmotic stress as a potent inflammatory stimulus by triggering pro-inflammatory cytokine release and inflammation. Under physiological conditions, the urine concentrating mechanism within the inner medullary region of the mammalian kidney exposes cells to high extracellular osmolarity. As such, renal cells have developed many adaptive strategies to compensate for increased osmolarity. Hyperosmotic stress is linked to many maladies, including acute and chronic, as well as local and systemic, inflammatory disorders. Hyperosmolarity triggers cell shrinkage, oxidative stress, protein carbonylation, mitochondrial depolarization, DNA damage, and cell cycle arrest, thus rendering cells susceptible to apoptosis. However, many adaptive mechanisms exist to counter the deleterious effects of hyperosmotic stress, including cytoskeletal rearrangement and up-regulation of antioxidant enzymes, transporters, and heat shock proteins. Osmolyte synthesis is also up-regulated and many of these compounds have been shown to reduce inflammation. The cytoprotective mechanisms and associated regulatory pathways that accompany the renal response to hyperosmolarity are found in many non-renal tissues, suggesting cells are commonly confronted with hyperosmotic conditions. Osmoadaptation allows cells to survive and function under potentially cytotoxic conditions. This review covers the pathological consequences of hyperosmotic stress in relation to disease and emphasizes the importance of considering hyperosmolarity in inflammation and disease progression.

Estrogen affects transcriptional status by activating its corresponding nuclear receptor, the estrogen receptor (ER). It can also induce rapid cellular reactions within a few minutes, and this feature cannot be explained by the transcription-mediated effects of estrogen. The latter mechanisms are called ‘non-genomic actions’ of estrogen. In contrast, the former classic modes of action came to be called ‘genomic actions’. One of the recent developments of research on estrogen was the substantiation of the non-genomic actions of estrogen; these were initially observed and reported as intriguing phenomena more than 40 years ago. The interacting molecules as well as the biological significance of non-genomic actions have now been shown. In the field of genomic actions, invention and spread of new technologies, including high-throughput sequencers, promoted a comprehensive view of estrogen-mediated transcriptional regulation.

The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A–G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipids holds great promise in the prevention of cardiovascular diseases. Inhibition of SR expression using a combined gene therapy and RNA interference strategy also appears to be an option for long-term therapy. The present review focuses on the involvement of SRs in atherosclerosis, thrombosis, and other cardiovascular diseases. Moreover, the role of SRs is not restricted to vascular lesions; it is also implicated in a number of different cellular functions.

Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulation. In addition, activations of BAT have important implications for energy homeostasis due to the metabolic consumption of energy reserves entailed in the production of heat in this tissue. In this conceptual overview, we describe the role of orexins/hypocretins within the central nervous system in the modulation of thermogenesis in BAT under several physiological conditions. Within this framework, we consider potential neural mechanisms underlying the pathological conditions associated with the absence of the central orexinergic modulation of BAT thermogenesis and energy expenditure. Overall, the experimental basis for our understanding of the role of central orexin in regulating body temperature and energy homeostasis provides an illustrative example that highlights several general principles and caveats that should help guide future investigations of the neurochemical regulation of thermogenesis and metabolism.

Telomeres, the physical ends of linear eukaryotic chromosomes, protect chromosome ends from end fusions and degradation. Telomere length is tightly regulated to ensure that telomeres are neither too short nor too long. Short telomeres are preferentially elongated by the enzyme telomerase. In the absence of telomerase, telomeres progressively shorten with each round of cell division. Critically shortened telomeres lose their ability to protect chromosome ends, inducing cell cycle arrest and senescence. While the consequences and cellular response to short telomeres are frequently explored, long telomeres also pose problems and cells have evolved mechanisms to shorten over-elongated telomeres. These aspects of long telomeres are discussed in this short conceptual overview.