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PubMed2005

Gene expression patterns in bone after 4 days of hind-limb unloading in two inbred strains of mice.

INTRODUCTION: An improved understanding of the interdependence of transcriptional and genomic control of bone loss is critical for the design of effective and safe countermeasures for osteoporosis in space and on Earth. In an effort to test whether molecular pathways modulating the loss of functional weight bearing are dependent on genetic makeup, we quantified the differential expression of genes critical to the early stages of bone remodeling in two different strains of mice. METHODS: Adult (4-mo-old) female BALB/cByJ (BALB) and C3H/HeJ (C3H) mice, strains with different sensitivities to unloading, were subjected to hind-limb unloading (HLU) or normal cage activities. RNA was extracted from the tibia following 4 d of HLU and expression levels were determined. RESULTS: In the BALB mice, HLU significantly altered transcriptional levels of osterix (-36%), alkaline phosphatase (-36%), osteonectin (-44%), collagen type 1 (-55%), MMP2 (-36%), osteocalcin (-68%), and osteopontin (+28%). This expression pattern was highly correlated (R2 = 0.75) with altered expression levels in the C3H mice, but the magnitude of altered mRNA levels was less than half of those in the BALB mice. These strain-specific changes in gene expression were consistent with the differential changes in bone formation, as determined in a second group of BALB and C3H mice. DISCUSSION AND CONCLUSIONS: These data indicate that genetics may influence the absolute changes in gene expression of genes during spaceflight, but that the molecular pathways targeted by countermeasures of bone loss may not need to be specific to an individual's genetic makeup.

Animals↗
PubMed2006

Deviant effects in molecular reaction pathways.

In biological networks, any manifestations of behaviors substantially 'deviant' from the predictions of continuous-deterministic classical chemical kinetics (CCK) are typically ascribed to systems with complex dynamics and/or a small number of molecules. Here we show that in certain cases such restrictions are not obligatory for CCK to be largely incorrect. By systematically identifying properties that may cause significant divergences between CCK and the more accurate discrete-stochastic chemical master equation (CME) system descriptions, we comprehensively characterize potential CCK failure patterns in biological settings, including consequences of the assertion that CCK is closer to the 'mode' rather than the 'average' of stochastic reaction dynamics, as generally perceived. We demonstrate that mechanisms underlying such nonclassical effects can be very simple, are common in cellular networks and result in often unintuitive system behaviors. This highlights the importance of deviant effects in biotechnologically or biomedically relevant applications, and suggests some approaches to diagnosing them in situ.

Biotechnology↗
PubMed2007

Cytogenetic abnormalities in MALT lymphomas and their precursor lesions from different organs. A fluorescence in situ hybridization (FISH) study.

AIMS: To analyse the possible activation of distinct molecular pathways in mucosa-associated lymphoid tissue (MALT) lymphoma, we determined the prevalence of trisomies 3, 12, 18 in MALT lymphomas from different organs, as well as the prevalence of translocations of the MALT1 gene in a subset of primary breast MALT lymphomas. We compared the numerical cytogenetic alterations in lymphomas, precursor lesions and in normal non-haematolymphoid tissue from the same organs. METHODS AND RESULTS: Forty-two samples of paraffin-embedded tissue (29 MALT lymphomas from stomach, breast, parotid and thyroid; two Sjögren's syndrome; two Hashimoto's thyroiditis and nine reactive samples) were studied by fluorescence in situ hybridization (FISH). Analysed together, the cases of gastric, parotid and thyroid MALT lymphomas presented trisomy 3 in 46%, trisomy 12 in 28% and trisomy 18 in 21% of the cases. In contrast to other locations, trisomy 3 was not present in the majority of the cases of primary breast MALT lymphomas. None of the nine breast cases presented MALT1 gene rearrangements. Half of the cases of preneoplastic lesions exhibited trisomy 3 and trisomy 12; none exhibited trisomy 18. CONCLUSIONS: Trisomy 3 is the most frequent numerical abnormality in gastric, parotid and thyroid but not in primary breast MALT lymphomas. MALT1 gene rearrangements are also rare in this location, suggesting that distinct molecular pathways may be activated in breast cases.

Chromosome Aberrations↗
PubMed2002

Development of a highly specialized cDNA array for the study and diagnosis of epithelial ovarian cancer.

Ovarian cancer is a major cause of cancer death in women. Unfortunately, the molecular pathways underlying ovarian cancer progression are poorly understood, making the development of novel diagnostic and therapeutic strategies difficult. On the basis of our previous observations obtained from serial analysis of gene expression, we have constructed a specialized cDNA array for the study of ovarian cancer. Small, specialized arrays have several practical advantages and can reveal information that is lost in the "noise" generated by irrelevant genes present in larger arrays. The array, which we named Ovachip, contains 516 cDNAs chosen from our serial analysis of gene expression and cDNA array studies for their relevance to ovarian cancer. The gene expression patterns revealed with the Ovachip are highly reproducible and extremely consistent among the different ovarian specimens tested. This array was extremely sensitive at differentiating ovarian cancer from colon cancer based on expression profiles. The Ovachip revealed clusters of coordinately expressed genes in ovarian cancer. One such cluster, the IGF2 cluster, is particularly striking and includes the insulin-like growth factor II, the cisplatin resistance-associated protein, the checkpoint suppressor 1, the cyclin-dependent kinase 6, and a protein tyrosine phosphatase receptor. We also identified a cluster of down-regulated genes that included the cyclin-dependent kinase 7 and cyclin H. Thus, the Ovachip allowed us to identify previously unidentified clusters of differentially expressed genes that may provide new paradigms for molecular pathways important in ovarian malignancies. Because of the relevance of the arrayed genes, the Ovachip may become a powerful tool for investigators in the field of ovarian cancer and may facilitate progress in understanding the etiology of this disease and in its clinical management.

Carcinoma, Papillary↗
PubMed2005

Mouse p10, an alternative spliced form of p15INK4b, inhibits cell cycle progression and malignant transformation.

The INK4 family of proteins negatively regulates cell cycle progression at the G(1)-S transition by inhibiting cyclin-dependent kinases. Two of these cell cycle inhibitors, p16(INK4A) and p15(INK4B), have tumor suppressor activities and are inactivated in human cancer. Interestingly, both INK4 genes express alternative splicing variants. In addition to p16(INK4A), the INK4A locus encodes a splice variant, termed p12--specifically expressed in human pancreas--and ARF, a protein encoded by an alternative reading frame that acts as a tumor suppressor through the p53 pathway. Similarly, the human INK4B locus encodes the p15(INK4B) tumor suppressor and one alternatively spliced form, termed as p10. We show here that p10, which arises from the use of an alternative splice donor site within intron 1, is conserved in the mouse genome and is widely expressed in mouse tissues. Similarly to mouse p15(INK4B), p10 expression is also induced by oncogenic insults and transforming growth factor-beta treatment and acts as a cell cycle inhibitor. Importantly, we show that mouse p10 is able to induce cell cycle arrest in a p53-dependent manner. We also show that mouse p10 is able to inhibit foci formation and anchorage-independent growth in wild-type mouse embryonic fibroblasts, and that these antitransforming properties of mouse p10 are also p53-dependent. These results indicate that the INK4B locus, similarly to INK4A-ARF, harbors two different splicing variants that can be involved in the regulation of both the p53 and retinoblastoma pathways, the two major molecular pathways in tumor suppression.

Alternative Splicing↗
PubMed1997

Characterization of the aromatic hydrocarbon receptor gene and its expression in Atlantic tomcod.

Cytochrome P4501A1 (CYP1A1) mRNA is not inducible in Atlantic tomcod from the Hudson River that are treated with halogenated aromatic hydrocarbons (HAHs). In contrast, CYP1A1 mRNA is inducible in Hudson River tomcod that are treated with polycyclic aromatic hydrocarbons (PAHs) and in tomcod that are collected from cleaner rivers and treated with HAHs or PAHs. We hypothesize that CYP1A1 transcription is inhibited in Hudson River tomcod because of down-regulation of the aromatic hydrocarbon receptor (AhR) pathway and that separate molecular pathways modulate CYP1A1 transcription in fish treated with HAHs and PAHs. We initially evaluated levels of hepatic nuclear protein binding at enhancer elements (DREs) in the regulatory region of tomcod CYP1A1. No difference in levels of protein binding was observed between tomcod from the Hudson and Miramichi (cleaner) rivers that were untreated or were treated with benzo[a]pyrene. In contrast, levels of protein binding were lower in tomcod from the Hudson River that were treated with TCB than in similarly treated fish from the Miramichi River, suggesting differences between the populations in the structure or expression of AhR pathway molecules. To address this possibility, AhR DNA sequences were characterized from tomcod cDNA and genomic DNA libraries. In tomcod and mammals, AhR is represented by 11 exons, overall peptide sizes are similar, and amino acid sequences at basic, helix-loop-helix, PAAS A, and PAAS B domains are highly conserved. In contrast, little similarity was observed between tomcod and mammals in the sizes or sequences of AhR exons 10 and 11, including the absence in tomcod of glutamine-rich domains. No differences in levels of hepatic AhR mRNA were observed between the two populations or treatment groups when tomcod were untreated or were treated with aromatic hydrocarbons. In contrast, variation in levels of AhR mRNA expression was observed among tomcod tissues; however, no relationship was observed between levels of AhR mRNAs and CYP1A1 mRNAs in tissues from chemically or vehicle control-treated fish. RFLP analysis revealed extensive variation in exons 10 and 11 of AhR cDNA among tomcod from different rivers. Our results suggest that variation between tomcod populations in CYP1A1 mRNA inducibility is reflected by differences in levels of inducible hepatic protein binding to DREs. However, levels of hepatic AhR mRNA are not down-regulated in the Hudson River population, are not affected by AH treatments, and levels of AhR mRNA expression are not responsible for the differential inducibility of CYP1A1 transcription.

Animals↗
PubMed1998

Parallel molecular genetic pathways operate during CNS metamorphosis in Drosophila.

Insect metamorphosis provides a valuable model for studying mechanisms of steroid hormone action on the nervous system during a dynamic phase of functional remodeling. The Drosophila Broad Complex (BRC) holds a pivotal position in the gene expression cascade triggered by the molting hormone 20-hydroxyecdysone (20E) at the onset of metamorphosis. We previously demonstrated that the BRC, which encodes a family of zinc-finger transcription factors, is essential for transducing 20E signals into the morphogenetic movements and cellular assembly that alter the CNS from juvenile to adult form and function. We set out to examine the relationship of BRC to two other genes, IMP-E1 and Deformed (Dfd), involved in the metamorphic transition of the CNS. Representatives of the whole family of BRC transcript isoforms accumulate in the CNS during the larval-to-pupal transition and respond directly to 20E in vitro. IMP-E1 is also directly regulated by 20E, but its induction is independent of BRC, revealing that 20E works through at least two pathways in the CNS. DFD expression is also independent of BRC function. Surprisingly, BRC and DFD proteins are expressed in distinct, nonoverlapping subsets of neuronal nuclei of the subesophageal ganglion even though both are required for its migration into the head capsule. This suggests that the segment identity and ecdysone cascades operate in parallel to control region-specific reorganization during metamorphosis.

Animals↗
PubMed2004

The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress.

The induction of many antioxidant and phase II drug-metabolizing enzymes by phenolic antioxidants and electrophilic compounds is regulated at the transcriptional level. The response to these compounds is mediated by the cis-acting antioxidant response element (ARE) found in the promoter of the encoding genes. The transcription factor NF-E2-related factor 2, or Nrf2, has emerged as the central protein that binds to the ARE to activate gene transcription. Data from many studies indicate that Nrf2 is constitutively and ubiquitously expressed in a number of tissues and cell lines and is thus responsible for the low-level expression of its target genes observed under physiological conditions. However, in cells exposed to oxidative stress, Nrf2 activity is increased, further driving the transcriptional activation of genes whose expression is essential to control cellular redox homeostasis. Recent studies suggest that the activation of Nrf2 involves a coordinated process and is regulated at multiple levels. Nrf2 activity is believed to be repressed through the binding of the cytoskeleton-associated protein Keap1, and its activation involves mechanisms that interfere with this interaction. Activation of Nrf2 has also been demonstrated to be dependent on mechanisms that mediate its stabilization. In this review, the mechanisms controlling this activation process as reported in recent studies will be examined and discussed, with particular emphasis on those affecting Nrf2 stability at the molecular level.

Animals↗
PubMed2002

Targeted expression of tetanus toxin: a new tool to study the neurobiology of behavior.

Over the past few decades, the explosion of molecular genetic knowledge, particularly in the fruit fly Drosophila melanogaster, has led to the identification of a large number of genes, which, when mutated, directly or indirectly affect fly behavior. Beyond the genetic and molecular characterization of genes and their associated molecular pathways, recent advances in molecular genetics also have allowed the development of new tools dedicated more directly to the dissection of the neural bases for various behaviors. In particular, the conjunction of the development of two techniques--the enhancer-trap detection system and the targeted gene expression system, based on the yeast GAL4 transcription factor--has led to the development of the binary enhancer-trap P[GAL4] expression system, which allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. Thus, this development, in addition to allowing the anatomical characterization of neuronal circuitry, also allows, via the expression of tetanus toxin light chain (known to specifically block synaptic transmission), an investigation of the role of specific neurons in certain behaviors. Using this system of "toxigenetics," several forms of behavior--from those mediated by sensory systems, such as olfaction, mechanoreception, and vision, to those mediated by higher brain function, such as learning, memory and locomotion--have been studied. These studies aim to map neuronal circuitry underlying specific behaviors and thereby unravel relevant neurophysiological mechanisms. The advantage of this approach is that it is noninvasive and permits the investigation of behavior in the free moving animal. We review a number of behavioral studies that have successfully employed this toxigenetic approach, and we hope to persuade the reader that transgenic tetanus toxin light chain is a useful and appropriate tool for the armory of neuroethologists.

Animals↗
PubMed1997

Colorectal carcinogenesis: from chromosomal evolution pathways to molecular pathogenesis.

Since the mid-1980s, research in the field of colorectal carcinogenesis has seen a series of breakthroughs such, as the process of loss of heterozygosity for large chromosomal segments and the consequent characterization of a series of suppressor genes considered to be the targets of the allelic deletions. More recently, a new perspective has been opened, with the discovery of germinal mutations of genes involved in mismatch repair in certain inherited forms of the disease. Through the retrospective analysis of our data on colorectal adenomas and cancers, we have tried to critically reassess a number of theoretical considerations relating to the instability of the genome viewed at the chromosome level and its consequence on tumor progression.

Adenoma↗
PubMed2000

Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats.

Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus, the entorhinal cortex, anterior cingulate cortex, posterior parietal cortex, or the basolateral complex of the amygdala. The animals were trained in one-trial step-down inhibitory avoidance and tested 24 h later. Prior (10 min) to the retention test, through the cannulae, they received 0.5 microl infusions of a vehicle (2% dimethylsulfoxide in saline), or of the following drugs dissolved in the vehicle: the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5, 2.0 or 5.0 microg), the AMPA receptor blocker, 6,7-dinitroquinoxaline-2,3 (1H,4H)dione (DNQX, 0.4 or 1.0 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG, 0.5 or 2.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the PKA stimulant, Sp-cAMPs (0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK), PD098059 (10 or 50 microM). All these drugs, at the same doses, had been previously found to alter long-term memory formation of this task. Here, retrieval test performance was blocked by DNQX, MCPG, Rp-cAMPs and PD098059 and enhanced by Sp-cAMPs infused into CA1 or the entorhinal cortex. The drugs had similar effects when infused into the parietal or anterior cingulate cortex, except that in these two areas AP5 also blocked retrieval, and in the cingulate cortex DNQX had no effect. Infusions into the basolateral amygdala were ineffective except for DNQX, which hindered retrieval. None of the treatments that affected retrieval had any influence on performance in an open field or in a plus maze; therefore, their effect on retention testing can not be attributed to an influence on locomotion, exploration or anxiety. The results indicate that the four cortical regions studied participate actively in, and are necessary for, retrieval of the one-trial avoidance task. They require metabotropic and/or NMDA glutamate receptors and PKA and MAPK activity. In contrast, the basolateral amygdala appears to participate only through a maintenance of its regular excitatory transmission mediated by glutamate AMPA receptors.

2-Amino-5-phosphonovalerate↗
PubMed2006

Signalling pathways and molecular interactions of NOD1 and NOD2.

The NOD (nucleotide-binding oligomerization domain) proteins NOD1 and NOD2 have important roles in innate immunity as sensors of microbial components derived from bacterial peptidoglycan. The importance of these molecules is underscored by the fact that mutations in the gene that encodes NOD2 occur in a subpopulation of patients with Crohn's disease, and NOD1 has also been shown to participate in host defence against infection with Helicobacter pylori. Here, we focus on the molecular interactions between these NOD proteins and other intracellular molecules to elucidate the mechanisms by which NOD1 and NOD2 contribute to the maintenance of mucosal homeostasis and the induction of mucosal inflammation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Molecular genetic pathways in Parkinson's disease: a review.

Major progress has been made in the last decade in understanding the genetic basis of PD (Parkinson's disease) with five genes unequivocally associated with disease. As a result, multiple pathways have been implicated in the pathogenesis of PD, including proteasome impairment and mitochondrial dysfunction. Although Mendelian genetics has been successful in establishing a genetic predisposition for familial PD, this has not been reiterated in the sporadic form. In fact no genetic factors have been unequivocally associated with increased risk for sporadic PD. The difficulty in identifying susceptibility factors in PD has not only been because of numerous underpowered studies, but we have been unable to dissect out the genetic component in a multifactorial disease. This review aims to summarize the genetic findings within PD.

Chromosome Mapping↗
PubMed1997

Cellular and molecular neurosurgery: pathways from concept to reality--part II: vector systems and delivery methodologies for gene therapy of the central nervous system.

Different vector systems that have been used and/or specifically developed for central nervous system (CNS) gene transfer studies are briefly discussed along with their advantages and disadvantages with respect to potential clinical application. These include retroviruses, recombinant herpes simplex virus, adenoviruses, adenoassociated viruses, encapsulation of plasmid deoxyribonucleic acid into cationic liposomes, and neural and oliogodendroglial stem cells. Particular attention has been paid to relate the modality of a specific CNS gene therapy to the strategy for adequate delivery of genetic material to the brain for either global or localized CNS neurodegenerative chronic disorder, as well as for CNS tumors and stroke. Techniques to circumvent the "impermeable" blood-brain barrier and how to breach the more versatile blood-brain-tumor barrier to deliver the genetic material to the target CNS cells are reviewed and include the following: 1) local stereotactic CNS injection/infusion of viral vectors, administration of vector producer cells, or cell replacement; 2) local administration of genetic material into the cerebrospinal fluid ventriculocisternal system; 3) osmotic opening of the blood-brain barrier; 4) local intra-arterial infusion; and 5) administration of blood-brain-tumor barrier permeabilizers, such as a bradykinin B2 agonist RMP-7. It is concluded that gene therapy for several brain disorders holds great potential, as suggested mainly by in vitro experiments and, to some extent, by a limited number of animal experiments. However, several drawbacks currently hamper the application of gene therapy under the clinical setting. The problems associated with gene therapy that still present major obstacles are as follows: 1) inefficient transfection of host cells by viral vectors; 2) restricted delivery of genetic material across vascular barriers of the CNS and brain tumors; 3) nonselective expression of the transgene; and 4) in situ CNS regulation of the transgene expression in a therapeutically controlled manner, as imposed by the course and phenotype of the CNS disease.

Animals↗