Dysregulation of TCTP in Biological Processes and Diseases

Translationally controlled tumor protein (TCTP), also called histamine releasing factor (HRF) or fortilin, is a multifunctional protein present in almost all eukaryotic organisms. TCTP is involved in a range of basic cell biological processes, such as promotion of growth and development, or cellular defense in response to biological stresses. Cellular TCTP levels are highly regulated in response to a variety of physiological signals, and regulatory mechanism at various levels have been elucidated. Given the importance of TCTP in maintaining cellular homeostasis, it is not surprising that dysregulation of this protein is associated with a range of disease processes. Here, we review recent progress that has been made in the characterisation of the basic biological functions of TCTP, in the description of mechanisms involved in regulating its cellular levels and in the understanding of dysregulation of TCTP, as it occurs in disease processes such as cancer

A discrete inhomogeneous model for the yeast cell cycle

We study the robustness and stability of the yeast cell regulatory network by using a general inhomogeneous discrete model. We find that inhomogeneity, on average, enhances the stability of the biggest attractor of the dynamics and that the large size of the basin of attraction is robust against changes in the parameters of inhomogeneity. We find that the most frequent orbit, which represents the cell-cycle pathway, has a better biological meaning than the one exhibited by the homogeneous model.Comment: 5 pages, 1 figur

TPT1/TCTP-regulated pathways in phenotypic reprogramming

Evolutionary conserved and pleiotropic, the TPT1/TCTP gene (translationally controlled tumor protein, also called HRF, fortilin), encodes a highly structured mRNA shielded by ribonucleoproteins and closely resembling viral particles. This mRNA activates, as do viruses, protein kinase R (PKR). The TPT1/TCTP protein is structurally similar to mRNA-helicases and MSS4. TPT1/TCTP has recently been identified as a prognostic factor in breast cancer and a critical regulator of the tumor suppressor p53 and of the cancer stem cell (SC) compartment. Emerging evidence indicates that TPT1/TCTP is key to phenotypic reprogramming, as shown in the process of tumor reversion and possibly in pluripotency. We provide here an overview of these diverse functions of TPT1/TCTP

q-Breathers in Discrete Nonlinear Schroedinger arrays with weak disorder

Nonlinearity and disorder are key players in vibrational lattice dynamics, responsible for localization and delocalization phenomena. $q$-Breathers -- periodic orbits in nonlinear lattices, exponentially localized in the reciprocal linear mode space -- is a fundamental class of nonlinear oscillatory modes, currently found in disorder-free systems. In this paper we generalize the concept of $q$-breathers to the case of weak disorder, taking the Discrete Nonlinear Schr\"{o}dinger chain as an example. We show that $q$-breathers retain exponential localization near the central mode, provided that disorder is sufficiently small. We analyze statistical properties of the instability threshold and uncover its sensitive dependence on a particular realization. Remarkably, the threshold can be intentionally increased or decreased by specifically arranged inhomogeneities. This effect allows us to formulate an approach to controlling the energy flow between the modes. The relevance to other model arrays and experiments with miniature mechanical lattices, light and matter waves propagation in optical potentials is discussed.Comment: 5 pages, 3 figure

Epigenetic reprogramming of breast cancer cells with oocyte extracts

<p>Abstract</p> <p>Background</p> <p>Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis.</p> <p>Results</p> <p>We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts.</p> <p>Conclusions</p> <p>This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.</p

Anti-Neuroinflammatory effects of the extract of Achillea fragrantissima

<p>Abstract</p> <p>Background</p> <p>The neuroinflammatory process plays a central role in the initiation and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and involves the activation of brain microglial cells. During the neuroinflammatory process, microglial cells release proinflammatory mediators such as cytokines, matrix metalloproteinases (MMP), Reactive oxygen species (ROS) and nitric oxide (NO). In the present study, extracts from 66 different desert plants were tested for their effect on lipopolysaccharide (LPS) - induced production of NO by primary microglial cells. The extract of <it>Achillea fragrantissima </it>(<it>Af</it>)<it/>, which is a desert plant that has been used for many years in traditional medicine for the treatment of various diseases, was the most efficient extract, and was further studied for additional anti-neuroinflammatory effects in these cells.</p> <p>Methods</p> <p>In the present study, the ethanolic extract prepared from <it>Af </it>was tested for its anti-inflammatory effects on lipopolysaccharide (LPS)-activated primary cultures of brain microglial cells. The levels of the proinflammatory cytokines interleukin1β (IL-1β) and tumor necrosis factor-α (TNFα) secreted by the cells were determined by reverse transcriptase-PCR and Enzyme-linked immunosorbent assay (ELISA), respectively. NO levels secreted by the activate cells were measured using Griess reagent, ROS levels were measured by 2'7'-dichlorofluorescein diacetate (DCF-DA), MMP-9 activity was measured using gel zymography, and the protein levels of the proinflammatory enzymes cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) were measured by Western blot analysis. Cell viability was assessed using Lactate dehydrogenase (LDH) activity in the media conditioned by the cells or by the crystal violet cell staining.</p> <p>Results</p> <p>We have found that out of the 66 desert plants tested, the extract of <it>Af </it>was the most efficient extract and inhibited ~70% of the NO produced by the LPS-activated microglial cells, without affecting cell viability. In addition, this extract inhibited the LPS - elicited expression of the proinflammatory mediators IL-1β, TNFα, MMP-9, COX-2 and iNOS in these cells.</p> <p>Conclusions</p> <p>Thus, phytochemicals present in the <it>Af </it>extract could be beneficial in preventing/treating neurodegenerative diseases in which neuroinflammation is part of the pathophysiology.</p

Axonal Regeneration and Neuronal Function Are Preserved in Motor Neurons Lacking ß-Actin In Vivo

The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA), suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO) to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo

Cancer: evolutionary, genetic and epigenetic aspects

There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy