Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “molecular pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources
PubMed2003

Cellular and molecular mechanisms of neuronal migration in neocortical development.

The complicated mammalian brain structure arises from accurate movements of neurons from their birthplace to their final locations. Detailed observation of this migration process by various methods revealed that neuronal migration is highly motile and that there are different modes of migration. Moreover, mouse mutants or human disorders that disrupt normal migration have provided significant insights into molecular pathways that control the neuronal migration. Although our knowledge is still fragmentary, it is becoming clear that various molecules are participating in this process. In this review, we outline about the cellular and molecular mechanisms of neuronal migration in the cerebral cortex.

Animals↗
PubMed2004

Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.

BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apoptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphorylation events; however, the extent to which phosphorylation-activated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.

Apoptosis↗
PubMed2006

Gene expression profile differences in left and right liver lobes from mid-gestation fetal baboons: a cautionary tale.

Interpretation of gene array data presents many potential pitfalls in adult tissues. Gene array techniques applied to fetal tissues present additional confounding pitfalls. The left lobe of the fetal liver is supplied with blood containing more oxygen than the right lobe. Since synthetic activity and cell function are oxygen dependent, we hypothesized major differences in mRNA expression between the fetal right and left liver lobes. Our aim was to demonstrate the need to evaluate RNA samples from both lobes. We performed whole genome expression profiling on left and right liver lobe RNA from six 90-day gestation baboon fetuses (term 180 days). Comparing right with left, we found 875 differentially expressed genes - 312 genes were up-regulated and 563 down-regulated. Pathways for damaged DNA binding, endonuclease activity, interleukin binding and receptor activity were up-regulated in right lobe; ontological pathways related to cell signalling, cell organization, cell biogenesis, development, intracellular transport, phospholipid metabolism, protein biosynthesis, protein localization, protein metabolism, translational regulation and vesicle mediated transport were down-regulated in right lobe. Molecular pathway analysis showed down-regulation of pathways related to heat shock protein binding, ion channel and transporter activities, oxygen binding and transporter activities, translation initiation and translation regulator activities. Genes involved in amino acid biosynthesis, lipid biosynthesis and oxygen transport were also differentially expressed. This is the first demonstration of RNA differences between the two lobes of the fetal liver. The data support the argument that a complete interpretation of gene expression in the developing liver requires data from both lobes.

Animals↗
PubMed2004

Advanced glycation and advanced lipoxidation: possible role in initiation and progression of diabetic retinopathy.

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs/ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs/ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation/lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE/ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE/ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.

Animals↗
PubMed2006

Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.

INTRODUCTION: Malnutrition is a common problem in cancer patients. Its incidence varies according to disease stage (between 15 and 90%) and is considered a possible prognostic factor for therapeutic response and survival. It is also one of the causes contributing to the increase in morbidity and mortality in patients. Tumor cachexia is defined as a nutritional defect caused by tumor growth in the patient and presents as a significant weight loss. This weight loss is mainly caused by a degradation of skeletal muscle proteins. CONCLUSION: The ubiquitin-proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.

Anorexia↗
PubMed2002

The pathophysiology of thyroid-associated ophthalmopathy.

TAO is an inflammatory disease of the orbital tissues. The effects of inflammation, mediated through cytokine release, include proliferation of fibroblasts, increased deposition of extracellular matrix, and adipocyte differentiation and proliferation. As a result, edema, enlargement of the extraocular muscles, and increased volume of the orbital soft tissues occur with ensuing exophthalmos and, in some patients, compression of the optic nerve. Edema, inflammation, and late fibrosis, account for the decreased function of the extraocular muscles, despite relative preservation of the fibers themselves. The recruitment of T cells to the orbits of these patients may result from the expression of the target of the aberrant immune response in Graves' disease, the TSH receptor, in the orbits of patients with TAO. The orbital fibroblasts, especially those present within patients with TAO, may be more sensitive to the effects of cytokines, accounting for the frequent, and relatively selective, involvement of the orbit in Graves' disease. Insight into the cellular and molecular pathways proposed in this cascade introduces potential sites for new therapeutic approaches and understanding of the mechanisms of current treatments. Corticosteroids, used frequently in the treatment of TAO, have a detectable effect at the molecular level. While glucocorticoids do not directly influence extracellular matrix production [62] or baseline proliferation of orbital fibroblasts [27] they do attenuate the effect of several cytokines on inducing proliferation of these fibroblasts or extracellular matrix production, and this influence is greater in fibroblasts from TAO patients [27,36]. The consistent observation of early inflammation suggests that immunomodulation early in the course of the disease should be a primary goal of management of TAO. The elucidation of the specific cytokines that are released and active in the orbits of patients with TAO may aid in the development of more specific immunomodulatory therapies. Improved understanding of the pathophysiology of TAO may also help identify more rational approaches to treatment. For example, identification of the molecules involved in the inflammatory cascade which results in TAO may help predict progression of disease and identify specific treatment modalities which may benefit individual patients [11,70].

Graves Disease↗
PubMed2004

Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.

Animals↗
PubMed1999

Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells.

Members of the Hedgehog (Hh) family of secreted signaling proteins function as potent short-range organizers in animal development. Their range of action is limited by a C-terminal cholesterol tether and the upregulation of Patched (Ptc) receptor levels. Here we identify a novel segment-polarity gene in Drosophila, dispatched (disp), and demonstrate that its product is required in sending cells for normal Hh function. In the absence of Disp, cholesterol-modified but not cholesterol-free Hh is retained in these cells, indicating that Disp functions to release cholesterol-anchored Hh. Despite their opposite roles, Disp and Ptc share structural homology in the form of a sterol-sensing domain, suggesting that release and sequestration of cholesterol-modified Hh may be based on related molecular pathways.

Amino Acid Sequence↗
PubMed1995

An intramolecular recombination mechanism for the formation of the rRNA gene palindrome of Tetrahymena thermophila.

Large palindromic DNAs are found in a wide variety of eukaryotic cells. In Tetrahymena thermophila, a large palindrome is formed from a single rRNA gene (rDNA) during nuclear differentiation. We present evidence that a key step in the formation of the rDNA palindrome of T. thermophila involves homologous intramolecular recombination. Heteroduplex micronuclear rDNA molecules were constructed in vitro and microinjected into developing macronuclei, where they formed palindromes. Analysis of the resulting palindromes indicated that both strands of the microinjected rDNA are used to form the same palindrome. This study, together with a previous study (L. F. Yasuda and M.-C. Yao, Cell 67:505-516, 1991), is the first to define a molecular pathway of palindrome formation. The process is initiated by chromosome breakage at sites flanking the micronuclear rDNA. An intramolecular recombination reaction, guided by a pair of short inverted repeats located at the 5' end of the excised rDNA, covalently joins the two strands of micronuclear rDNA in a giant hairpin molecule. Bidirectional DNA replication converts the giant hairpin molecule to a palindrome. We suggest that the general features of this pathway are applicable to palindrome formation in other cell types.

Animals↗
PubMed2003

Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.

Although it is often presumed that the molecular pathways that underlie normal organogenesis are similar to those perturbed during carcinogenesis, few examples exist of tissue-specific regulatory genes that play central roles in both processes. In the case of the prostate gland, molecular genetic analyses have demonstrated that the Nkx3.1 homeobox gene plays an important role in normal differentiation of the prostatic epithelium and that its loss of function is an initiating event in prostate carcinogenesis. Thus, the Nkx3.1 homeobox gene provides a paradigm for understanding the relationship between normal differentiation and cancer, as well as a model for studying the roles of homeobox genes in these processes. Here, we review recent findings concerning the biological as well as biochemical function of this central regulator of prostate development and carcinogenesis.

Alternative Splicing↗
PubMed2004

Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts.

Clefts of the lip and/or palate (CL/P) are among the most common birth defects worldwide. The majority are non-syndromic where CL/P occurs in isolation of other phenotypes. Where one or more additional features are involved, clefts are referred to as syndromic. Collectively CL/P has a major clinical impact requiring surgical, dental, orthodontic, speech, hearing and psychological treatments or therapies throughout childhood. The etiology of CL/P is complex and thought to involve both major and minor genetic influences with variable interactions from environmental factors. Using a combination of gene targeting technology and traditional developmental techniques in both mouse and chick, significant progress has been made in the identification of numerous genes and gene pathways critical for craniofacial development. Despite this, it has been a particular source of frustration that mutation screening of specific candidates, association studies and even genome-wide scans have largely failed to reveal the molecular basis of human clefting. Nevertheless, some important findings have recently come from studies involving syndromic forms of the disorder. These include several genes which have now been shown to contribute a major effect on the etiology of CL/P. Furthermore, these genes can also be used to demonstrate a significant overlap between syndromic and non-syndromic CL/P. The study of these syndromic genes and their molecular pathways will provide a useful and informative route with which to gain a better understanding of human craniofacial pathology.

Cleft Lip↗
PubMed2005

Brief communication: morphoproteomic analysis of osteolytic Langerhans cell histiocytosis with therapeutic implications.

Morphoproteomics utilizes immunohistochemistry to identify protein analytes in tumor cells in order to uncover or confirm potential molecular pathways that may be essential to their proliferation, integrity, and histogenesis and that may serve as therapeutic targets. This communication illustrates the application of such an approach to osteolytic Langerhans cell histiocytosis and considers such molecular targets in the context of currently available therapies.

Histiocytes↗
PubMed2005

Blocking the PI3K/PKB pathway in tumor cells.

A substantial number of experimental and epidemiological studies support an important role for the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway in the biology of human cancers. Components of this signaling cascade have been found to be deregulated in a wide range of solid tumors and hematologic malignancies, and extensive anti-cancer therapeutic programs are now devoted to the identification of agents that specifically block this molecular pathway. This article focuses on the current knowledge of the alterations of the PI3K/PKB pathway in cancer cells and ongoing drug discovery efforts to therapeutically target it. Particular emphasis is placed on medicinal chemistry activities to identify and develop compounds able to modulate the kinase activity of its main molecular components.

Cell Line, Tumor↗
PubMed2000

In search of the MRX genes.

Mental retardation (MR) is one of the most common human disorders. MR may be just one of the clinical signs of a complex syndrome or it may be associated with metabolic disorders or with disorders of brain development, but in many patients [nonspecific MR (NSMR)], it is the only consistent clinical manifestation. It is expected that NSMR is caused by alterations in molecular pathways important for cognitive functions. Insights into NSMR have recently come from the study of X-linked MR as eight genes were identified during the last few years. This development has represented a fundamental breakthrough in our understanding of NSMR and of cognitive functions and has opened new perspectives in the study of MR. The new genes identified are a heterogeneous group, but it is very intriguing that they are all directly or indirectly involved in signaling pathways and that the majority are proteins that regulate members of the Ras superfamily of small GTP binding proteins.

Chromosome Mapping↗
PubMed2003

Myocardin mRNA is augmented in the failing myocardium: expression profiling in the porcine model and human dilated cardiomyopathy.

The implication of myocardin and homeodomain only protein (HOP) in combinatorial molecular pathways that guide heart development and cardio-specific gene expression has recently been reported. However, expression of these genes in the failing heart has not yet been investigated. This study was designed to elaborate a molecular profile of myocardin and HOP expression in the failing ventricular myocardium through the use of both explanted human heart samples and heart biopsies from neonatal piglets with doxorubicin-induced cardiomyopathy (Dox-CM). Myocardin and HOP mRNA levels were estimated by both northern blot hybridization and semiquantitative RT-PCR in human ventricular preparations in end-stage failure due to dilated cardiomyopathy (DCM), as well as in nonfailing donor hearts. Similar experiments were performed with ventricular samples from normal and Dox-treated neonatal piglets. The gene expression of brain natriuretic peptide (BNP) was used as a molecular marker of myocardial damage and failure. The study revealed the following novel findings: (1) myocardin transcripts are detected in neonatal human and pig hearts at lower levels than in mature cardiac tissues, (2) the myocardin transcript pool is significantly augmented in the failing human and porcine myocardium as compared to that in nonfailing heart samples, (3) in the failing human myocardium, increased levels of myocardin mRNA are associated with a diminished HOP transcript content, and (4) the inverse proportion in cardiac myocardin/HOP mRNA pools observed in explanted human hearts is also traceable in normal human heart and aorta. A possible dual consequence of increased myocardin and decreased HOP expression levels on serum response factor-dependent cardiac-specific expression in the normal heart and at heart failure is discussed. Therefore, increased abundance of the myocardin mRNA pool is judged to be a novel CM-related feature which, alone or in association with decreased HOP transcript levels, can be responsible for dysregulation of myocardin-mediated gene expression in failing myocardium.

Amino Acid Sequence↗
PubMedDate not supplied

Genes governing placental development.

The placenta is essential for fetal growth because it promotes the delivery of nutrients and oxygen from the maternal circulation. In mice, many gene mutations disrupt formation of the placenta, with specific effects at different times and on different components. Studies of these mutations are beginning to provide insights into both the molecular pathways required for formation of different placental substructures and the nature of intercellular interactions, between trophoblast, mesenchymal and vascular components, that regulate placental development. Conserved gene expression patterns in humans should enable the elucidation of the molecular basis of human placental dysfunction.

Allantois↗
PubMed2005

Diverse regulation of sensory signaling by C. elegans nPKC-epsilon/eta TTX-4.

Molecular and pharmacological studies in vitro suggest that protein kinase C (PKC) family members play important roles in intracellular signal transduction. Nevertheless, the in vivo roles of PKC are poorly understood. We show here that nPKC-epsilon/eta TTX-4 in the nematode Caenorhabditis elegans is required for the regulation of signal transduction in various sensory neurons for temperature, odor, taste, and high osmolality. Interestingly, the requirement for TTX-4 differs in different sensory neurons. In AFD thermosensory neurons, gain or loss of TTX-4 function inactivates or hyperactivates the neural activity, respectively, suggesting negative regulation of temperature sensation by TTX-4. In contrast, TTX-4 positively regulates the signal sensation of ASH nociceptive neurons. Moreover, in AWA and AWC olfactory neurons, TTX-4 plays a partially redundant role with another nPKC, TPA-1, to regulate olfactory signaling. These results suggest that C. elegans nPKCs regulate different sensory signaling in various sensory neurons. Thus, C. elegans provides an ideal model to reveal genetically novel components of nPKC-mediated molecular pathways in sensory signaling.

Amino Acid Sequence↗
PubMed1997

Craniosynostosis: genes and mechanisms.

Enlargement of the skull vault occurs by appositional growth at the fibrous joints between the bones, termed cranial sutures. Relatively little is known about the developmental biology of this process, but genetically determined disorders of premature cranial suture fusion (craniosynostosis) provide one route to the identification of some of the key molecules involved. Mutations of the MSX2, FGFR1, FGFR2, FGFR3 and TWIST genes yield new insights, both into normal and abnormal cranial suture biogenesis and into problems of broad interest, such as the conservation of molecular pathways in development, and mechanisms of mutation and dominance.

Amino Acid Sequence↗