Current Molecular Medicine - Volume 13, Issue 8, 2013

Tumor suppressor p53 maintains genome stability by regulating diverse cellular functions including cell cycle arrest, apoptosis, senescence and metabolic homeostasis. Mutations in the p53 gene occur in almost all human cancers with a frequency of up to 80%. However, it is only 20% in breast cancers, 18% in endometrial cancers and 1.5% in cervical cancers. Estrogen receptor alpha (ERα) plays a pivotal role in hormone-dependent cancer development and the status of ERα is used for designing treatment strategy and for prognosis. A closer look at the cross-talk between p53 and ERα has revealed that their activities are mutually regulated. This review will summarize the current body of knowledge on p53, ERα and ERβ in cancer. Clinical correlations between estrogen receptors and p53 status have also been reported. Thus, this review will discuss the relationship between p53 and ERs at both the molecular and clinical levels.

Glioblastoma is the most aggressive adult primary brain tumor. Although progress has been made in understanding the molecular mechanisms underlying these tumors, current treatments are ineffective. Recent studies have identified iNOS as a critical regulator of glial transformation downstream of EGFRvIII/STAT3 signaling, a key oncogenic pathway in glioblastoma. STAT3 directly binds the promoter of the iNOS gene and thereby stimulates its expression. Importantly, inhibition of iNOS by genetic and pharmacological approaches impedes glial cell proliferation, invasiveness, and tumor growth in vivo. iNOS expression is also elevated in a population of human brain tumor stem cells (BTSCs), and iNOS is required for BTSC proliferation and tumorigenesis. Together, these findings suggest that development of iNOS-targeted therapies may prove valuable in the treatment of glioblastoma. Here, we review our current understanding of iNOS signaling in the regulation of glioblastoma pathogenesis and the potential mechanisms by which iNOS inhibition might suppress the malignant behavior of these devastating tumors.

Skin is considered as the border defining the limits of the body from the external world and functions as a barrier between the two. In this capacity, it has evolved to be an integral part of the innate and adaptive immune system. Although many reviews have described skin inflammation and processes that lead to its clinical manifestations, we are not aware of any reviews that have focused on immunologic activity occurring in the absence of any visual inflammatory cues. In this review, we discuss the importance of subclinical inflammation in human skin and its relevance to innate immune surveillance under physiologic conditions. Reactive oxygen species generated by metabolic processes, ultraviolet radiation or oxidizers may damage cells, initiating proinflammatory cascades. In addition to serving as structural skin components, keratinocytes have significant immunologic activity: they secrete proinflammatory cytokines and mediators, including interleukin (IL)-1α, IL-6, IL-10, tumor necrosis factor-α and granulocyte-macrophage colony-stimulating factor. Infant skin is particularly susceptible to irritation, inflammation and infection, since skin barrier function is not fully developed after birth and continues to mature throughout the first few years of life. Non-invasive methods such as fluorescence spectroscopy, spectral imaging and diffuse reflectance spectroscopy, as well as minimally invasive tape stripping, can be used to assess subclinical inflammatory markers in vivo, including erythema, epidermal cell proliferation rate and cytokine concentrations. Appropriately formulated skin care products may help maintain skin barrier integrity and enhance its capacity. In the future, assessment of subclinical inflammation may help clinicians prevent acute or chronic inflammatory conditions of the skin.

Neutrophils are highly motile phagocytic cells that constitute the first line of defense of the innate immune system. Unlike the other innate immune cells, mature neutrophils fully equipped with an armory of granules are short lived cells which are differentiated and programmed from hematopoietic stem cells in the bone marrow. In blood, mature or nearly mature cells are devoid of proliferative potential. While the killing mechanisms of neutrophils have been the research focus in the past, attention was then directed toward granulocytopoiesis by the recent studies about the specfic functional states and exact regulatory mechanisms in neutrophil development and homeostasis. Here, we focus on the recent findings regarding the mechanisms that control the generation and homeostasis of neutrophils.

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

Matrix metalloproteinases (MMPs) are a family of tightly regulated, zinc-dependent proteases that degrade extracellular matrix (ECM), cell surface, and intracellular proteins. Vascular remodeling, whether as a function of normal physiology or as a consequence of a myriad of pathological processes, requires degradation of the ECM. Thus, the expression and activity of many MMPs are up-regulated in numerous conditions affecting the vasculature and often exacerbate vascular dysfunction. A growing body of evidence supports the rationale of using MMP inhibitors for the treatment of cardiovascular diseases, stroke, and chronic vascular dementia. This manuscript will examine promising targets for MMP inhibition in atherosclerosis and stroke, reviewing findings in preclinical animal models and human patient studies. Strategies for MMP inhibition have progressed beyond chelating the catalytic zinc to functional blocking antibodies and peptides that target either the active site or exosites of the enzyme. While the inhibition of MMP activity presents a rational therapeutic avenue, the multiplicity of roles for MMPs and the non-selective nature of MMP inhibitors that cause unintended side-effects hinder full realization of MMP inhibition as therapy for vascular disease. For optimal therapeutic effects to be realized, specific targets for MMP inhibition in these pathologies must first be identified and then attacked by potent and selective agents during the most appropriate timepoint.

β-thalassemias constitute hereditary blood disorders characterized by reduced or absence of β-globin synthesis resulting in mild to severe anemia, depending on the genotype. More than 200 mutations in the β-globin gene are responsible for their specific features leading to a very heterogeneous phenotype. Current therapies for β-thalassemia include blood transfusions, usually along with iron chelation and in selected cases with bone marrow transplantation (BMT) of HLA-matched hematopoietic stem cells (HSCs). However, these approaches are limited by factors, such as iron overload and donor availability, respectively. Since 2000, when globin lentiviral vectors (LVs) were first successfully tested for transfer efficiency of the therapeutic transgene, which led to disease amelioration in murine models, attention was drawn towards the improvement of such vectors for β-thalassemia gene therapy. Constantly improving vector design and efficient HSC manipulation led recently to the first successful clinical trial in France, which further proved that this genetic approach can be curative. Furthermore, improved new efficient vectors and methods to safely monitor integration sites and therapeutic transgene position effects, promise a new era for β-thalassemia gene therapy, with more and safer clinical trials yet to come.

Direct intercellular communication is mediated by gap junctions and their constitutive proteins, the connexins, which are organized in a hexameric arrangement forming a channel between adjacent cells. Connexins are essential for cell homeostasis and are also involved in many physiological processes such as cell growth, differentiation and death. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival and apoptosis, in which one connexin isoform, connexin 43, plays an essential role as evidenced by the targeted genetic deletion of Cx43 gene. A controlled balance of germ cell growth is a prerequisite to maintain either normal level of spermatozoa necessary for fertility and/or to limit an uncontrolled and anarchic germ cell proliferation, a major risk for germ cell tumor cell development. In the present review, we highlight the emerging role of connexins in testis pathogenesis, specifically in two intimately interconnected human testicular diseases: azoospermia with impaired spermatogenesis and testicular germ cell tumors, whose incidence increased during the last decades. This review proposes the gap junction protein connexin 43 as a new potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases.

Preeclampsia is a disease of high incidence in pregnant women which complicates pregnancy and may lead to the death of mother and baby. Preeclampsia is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction. Although the causes of disease have not been elucidated, it has been reported that high levels of endoglin, a TGF-β auxiliary co-receptor, and a soluble form of this protein, occur respectively in the placenta and plasma of women who develop the disease. In this review, the alterations in vasculogenesis and angiogenesis that occur during preeclampsia, the cellular and molecular mechanisms that lead to increased membrane bound endoglin expression and soluble endoglin release, including hypoxia and oxidative stress, and the possible pathogenic role of soluble endoglin in this disease have been analyzed.

Halitosis (bad breath) is estimated to influence more than half of the world's population with varying degree of intensity. More than 85% of halitosis originates from oral bacterial infections. Foul-smelling breath mainly results from bacterial production of volatile sulfur compounds (VSCs) such as hydrogen sulfide and methyl mercaptan. To date, major treatments for elimination of oral malodor include periodontal therapy combined with antibiotics or antimicrobial agents, and mechanical approaches including tooth and tongue cleaning. These treatments may transiently reduce VSCs but carry risks of generating toxicity, increasing resistant strains and misbalancing the resident human flora. Therefore, there is a need to develop alternative therapeutic modalities for halitosis. Plaque biofilms are the principal source for generating VSCs which are originally metabolized from amino acids during co-aggregation of oral bacteria. Blocking the bacterial coaggregation, therefore, may prevent various biofilm-associated oral diseases such as periodontitis and halitosis. Fusobacterium nucleatum (F. nucleatum), a Gram-negative anaerobe oral bacterium, is a main bacterial strain related to halitosis. Aggregation of F. nucleatum with other bacteria to form plaque biofilms in oral cavity causes bad breath. FomA, the major outer membrane protein of F. nucleatum, recruits other oral pathogenic bacteria such as Porphyromonas gingivalis (P. gingivalis) in the periodontal pockets. A halitosis vaccine targeting F. bacterium FomA significantly abrogates the enhancement of bacterial co-aggregation, biofilms, production of VSCs, and gum inflammation mediated by an inter-species interaction of F. nucleatum with P. gingivalis, which suggests FomA of F. nucleatum to be a potential target for development of vaccines or drugs against bacterial biofilm formation and its associated pathogenicities.

Pancreatic cancer has an extremely poor prognosis mainly due to lack of effective treatment options. Radiotherapy is mostly applied to locally advanced cases, although tumor radioresistance limits the effectiveness. Profilin1, a novel tumor suppressor gene, was reported to be down-regulated in various cancers and associated with tumor progression. The objective of this study was to demonstrate how profilin1 affected pancreatic cancer radiosensitivity. We showed profilin1 was down-regulated in pancreatic cancer cells after exposure to radiation, and re-expression of profilin1 suppressed tumor cell viability and increased DNA damage following irradiation. Further studies revealed that up-regulation of profilin1 facilitated apoptosis and repressed autophagy induced by irradiation, which might sensitize pancreatic cancer cells to radiation treatment. Our findings may provide a novel therapeutic strategy for sensitizing pancreatic cancer to radiotherapy.

Protein serine/threonine phosphatase-2A (PP-2A) is one of the key enzymes responsible for dephosphorylation in vertebrates. PP-2A-mediated dephosphorylation participates in many different biological processes including cell proliferation, differentiation, transformation, apoptosis, autophage and senescence. However, whether PP-2A directly controls animal development remains to be explored. Here, we present direct evidence to show that PP-2A displays important functions in regulating eye development of vertebrates. Using goldfish as a model system, we have demonstrated the following novel information. First, inhibition of PP-2A activity leads to significant death of the treated embryos, which is derived from blastomere apoptosis associated with enhanced phosphorylation of Bcl-XL at Ser-62, and the survived embryos displayed severe phenotype in the eye. Second, knockdown of PP-2A with morpholino oligomers leads to significant death of the injected embryos. The survived embryos from PP-2A knockdown displayed clear retardation in lens differentiation. Finally, overexpression of each catalytic subunit of PP-2A also causes death of majority of the injected embryos and leads to absence of goldfish eye lens or severely disturbed differentiation. Together, our results provide direct evidence that protein phosphatase-2A is important for normal eye development in goldfish.

Apoptosis is a widespread phenomenon and its dysregulation may result in a variety of human pathologies, such as cancer, autoimmune diseases and neurodegenerative disorders. CXXC-type zinc finger protein 5 (CXXC5) is commonly considered as a tumor suppressor undergoing deregulation or deletion in hematonosis. But it has implied involvement in apoptosis indirectly and the molecular mechanism remains unknown. In this study, we investigated CXXC5-induced apoptosis as well as its underlying mechanism. A fluorescence resonance energy transfer (FRET) assay suggested that CXXC5 induced cell death and caspase-3 activity in primary rat cortical neurons. Further colorimetric TUNEL assay, Hoechst staining and flow cytometric assay indicated a time-dependent apoptosis in which the activities of caspase-8 and caspase-3 were both regulated via CXXC5 according to enzymatic activity assay, Hoechst staining and Western blotting. Transcription reporter assay and Western blotting showed that CXXC5 resulted in activation of tumor necrosis factor-α (TNF-α), initiated the extrinsic apoptosis pathway and cross-linked with the intrinsic mitochondrial pathway. Being a bone morphogenetic protein 4 (BMP-4) downstream regulator, and also a transcription factor, cellular co-localization and co-immunoprecipitation results indicate that CXXC5 co-localized and interacted with Smads. Western blotting and nuclear fraction extraction implied that CXXC5 facilitated Smad3 phosphorylation and Smad4 nuclear translocation, and that co-expression of Smad together with CXXC5 resulted in higher TNF-α reporter activity. In sum, CXXC5 appears to regulate the TNF-α apoptosis pathway by associating with Smads.

MicroRNAs (miRNAs) participate in the regulation of myogenesis and muscle physiological function. Most skeletal muscles in vertebrates contain a mixture of fibertypes. So far, the regulatory mechanism of the miRNA in terms of controlling muscle phenotype is poorly understood. In the present study, we use Siniperca chuatsi as a model system and demonstrate that miRNAs are involved in regulating the physiological processes and metabolism of different muscle fibers in vertebrates. The miRNA transcriptomes of the white muscle, red muscle, and five other tissues from Siniperca chuatsi were profiled using Solexa deep sequencing. We characterized 186 conserved miRNAs and 3 novel miRNAs from the two small RNA libraries of white and red muscles. Among the 155 miRNAs overlapped between the two libraries, we identified 60 significantly expressed miRNAs between the two types of muscle fibers. Using integrative miRNA target-prediction and network-analysis approaches, an interaction network of differentially expressed and muscle-related miRNAs and their putative targets were constructed. Sch-miR-181a-5p that could act to control the performance of the different muscle fiber types by targeting the myostatin gene was identified.