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Results for “Critical Pathways”

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At least 973 records · Page 54Linked to original sources
PubMed2006

Divergent effects of the MEKK-1/JNK pathway on NB2a/d1 differentiation: some activity is required for outgrowth and stabilization of neurites but overactivation inhibits both phenomena.

c-Jun N-terminal kinase (JNK), along with its upstream activator MEKK-1, is typically thought of as a stress-activated kinase that mediates apoptosis. However, additional studies indicate that the MEKK-1/JNK pathway mediates critical aspects of neuronal survival and differentiation. Herein, we demonstrate that transfection of differentiated NB2a/d1 cells with a construct expression constitutively activated (ca) MEKK-1 increases levels of phospho-dependent neurofilament (NF) immunoreactivity within perikarya, while expression of a dominant-negative (dn) form of MEKK-1 decreases it. Steady-state levels of perikaryal phospho-NF immunoreactivity are reduced and the increase resulting from expression of caMEKK-1 is prevented, by the JNK inhibitor SP600125, suggesting that JNK is a major downstream effector of MEKK-1 on NF phosphorylation. Unexpectedly, both caMEKK-1 and dnMEKK-1 inhibited neuritogenesis as well as translocation of NFs into newly elaborated neurites. The JNK inhibitor SP600125 also inhibited NF transport in a dose-dependent manner. caMEKK-1 also prevented the increase in NF transport otherwise mediated by MAP kinase. Finally, both caMEKK-1 and dnMEKK-1 prevented initial neuritogenesis. These findings indicate that the MEKK-1/JNK pathway regulates critical aspects of initial outgrowth, and subsequent stabilization of axonal neurites.

Animals↗
PubMed2006

Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures.

Transforming growth factor beta (TGF-beta) modulates a number of cellular phenotypes as divergent as growth stimulation and growth inhibition. Although the Smad pathway is critical for many of these responses, recent evidence indicates that Smad-independent pathways may also have a critical role. One such protein previously shown to regulate TGF-beta action independent of the Smad proteins is the c-Abl nonreceptor tyrosine kinase. In the current study we determined that TGF-beta receptor signaling activates c-Abl kinase activity in a subset of fibroblast but not epithelial cultures. This cell type-specific response occurs in a membrane-proximal locale independent of receptor internalization and upstream of dynamin action. Although c-Abl activation by TGF-beta is independent of Smad2 or Smad3, it is prevented by inhibitors of phosphatidylinositol 3-kinase or PAK2. Thus, c-Abl represents a target downstream of phosphatidylinositol 3-kinase-activated PAK2, which differentiates TGF-beta signaling in fibroblasts and epithelial cell lines and integrates serine/threonine receptor kinases with tyrosine kinase pathways.

Animals↗
PubMed2003

Assembly of amyloid protofibrils via critical oligomers--a novel pathway of amyloid formation.

The amyloid formation of phosphoglycerate kinase (PGK) was investigated by static and dynamic light-scattering. The time-course of the scattering intensity and the hydrodynamic radius scale with initial monomer concentration in a linear fashion over a range of about 50 in concentration. This sets limits on theories for aggregation kinetics that can be used, and points towards irreversible, cascade type models. In addition, circular dichroism (CD) was used to monitor the transition between a predominantly alpha-helical spectrum to a beta-sheet enriched one. The time-course of the CD also proves to scale linearly with initial monomer concentration. Electron microscopy shows that small oligomers as well as protofibrils are present during aggregation. The found coupling between growth of intermediates and acquisition of beta-sheet structure is interpreted in terms of a generalized diffusion-collision model, where stabilization of beta-strands takes place by intermolecular interactions.

Amyloid↗
PubMedDate not supplied

Induced mouse chromosomal rearrangements as tools for identifying critical developmental genes and pathways.

Due to the rapid advances that have been made in molecular and genetic technology during the past decade, the genes associated with a large number of human hereditary diseases have been isolated and analyzed in detail. These cloned genes provide new tools for research geared toward a better understanding of normal human development, and also of the many ways that basic, essential morphologic pathways can be disturbed. Chromosomal rearrangements, especially deletions and translocations, have been especially beneficial in the mapping and isolation of human disease genes because of their visibility on both the cytogenetic and molecular levels. However, these useful types of mutations occur with low frequency in the human population. Chromosomal rearrangements can be induced relatively easily in mice, and several large, independent collections of translocation and deletion mutants have been generated in the course of risk-assessment and mutagenesis studies over the past several decades. Combined with new molecular technologies, these collections of mutant animals provide a means of gaining ready access to genes associated with developmental defects including craniofacial abnormalities, hydrocephaly, skeletal deformities, and complex neurologic disorders. As an illustration of this approach, we briefly review our progress in the study of three mutations associated with defects in palate development, juvenile growth, fitness and sterility, and neurologic development in mice, respectively.

Animals↗
PubMed2001

Ethylene glycol-mediated tubular injury: identification of critical metabolites and injury pathways.

Ethylene glycol (EG) intoxication produces multisystem organ injury, including acute renal failure. Although EG must be metabolized to toxic intermediates to induce organ damage, the specific metabolite(s) responsible and the underlying pathogenic mechanisms remain poorly defined. To explore these issues, isolated mouse proximal tubular segments (PTSs) were incubated with either varying doses of EG or its prime metabolites (glycolate, glycoaldehyde, glyoxylate, or oxalate for 15 to 60 minutes). Injury was assessed by the percentage of lactate dehydrogenase (LDH) release, LDH destruction, adenosine triphosphate (ATP) depletion, or membrane phospholipid degradation. Toxicities were also assessed in cultured HK-2 cells over 18 hours (by MTT assay). EG, glycolate, and oxalate did not induce overt PTS injury. Conversely, glyoxylate and glycoaldehyde were highly toxic, causing profound ATP depletion and LDH release. Glycoaldehyde also caused enzyme (LDH) and selected phospholipid degradation (phosphatidylethanolamine, phosphatidylserine). These changes were not seen with glyoxylate treatment. Acidosis (pH 6.8) and glycine (2 mmol/L) each blocked glyoxylate, but not glycoaldehyde toxicity, indicating differing injury pathways. Only glycoaldehyde and glyoxylate induced marked HK-2 cell death. We conclude that glycoaldehyde and glyoxylate are the principal metabolites responsible for EG nephrotoxicity and do so by causing ATP depletion and phospholipid and enzyme destruction. Glycine and acidosis, by-products of EG metabolism, can attenuate glyoxylate-mediated injury. This suggests that naturally occurring but incomplete protective pathways may be operative during the evolution of EG cytotoxicity.

Adenosine Triphosphate↗
PubMed2005

The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons.

Interferon signaling pathways are critical to both innate and adaptive immunity. We have demonstrated here that the inhibition of heat shock protein 90 (Hsp90) functions by small interfering RNAs or chemical inhibitors blocking interferon-induced gene expression. Hsp90 was required for signal transducers and activators of transcription 1 phosphorylation, and in its absence, Janus kinase (JAK) 1/2 were degraded by the proteosome. JAK1 interacts with Hsp90 and the CDC37 co-chaperone, and both interactions are destabilized by Hsp90 inhibitors. The biological consequences were suggested by experiments showing that T cell activation by interferon-gamma-primed macrophages and the antiviral response of interferons required Hsp90. We conclude that JAK1/2 are client proteins of Hsp90 and that Hsp90 and CDC37 play a critical role in types I and II interferon pathways.

Animals↗
PubMed2002

Co-regulation of pathogenesis with dimorphism and phenotypic switching in Candida albicans, a commensal and a pathogen.

Candida albicans, a common fungal pathogen of humans, can colonize in many diverse environments of the host and convert between a harmless commensal and a pathogen. Recent advances indicate that C. albicans uses a common set of conserved pathways to regulate dimorphism, mating and phenotypic switching. Major pathways known to regulate dimorphism include a mitogen-activated protein (MAP) kinase pathway through Cph1, the cAMP-dependent protein kinase pathway via Efg1, and Tup1-mediated repression through Rfg1 and Nrg1. The Cph1-mediated MAP kinase pathway is critical for the mating process, while all three pathways are implicated in the regulation of white-opaque switching. All these developmental pathways regulate the expression of hypha-specific and/or phase-specific genes. A high proportion of hypha-specific genes and phase-specific genes encode proteins that contribute directly or indirectly to pathogenesis and virulence of C. albicans. Therefore, virulence genes are co-regulated with cell morphogenesis. This supports a previous notion that the unique aspects of C. albicans commensalism and pathogenesis may lie in the developmental programs of dimorphism and phenotypic switching.

Candida albicans↗
PubMed2004

Expression profiling upon Nex1/MATH-2-mediated neuritogenesis in PC12 cells and its implication in regeneration.

The expression of Nex1 peaks during brain development when neurite outgrowth and synaptogenesis are highly active. We previously showed that Nex1 is a critical effector of the nerve growth factor (NGF) pathway and its overexpression results in spontaneous neuritogenesis. Furthermore, the PC12-Nex1 cells exhibit accelerated neurite extension upon NGF exposure, and have the capacity to regenerate neurites in the absence of NGF. In this study, we identify the repertoire of genes targeted by Nex1 to unravel the molecular mechanisms by which Nex1 promotes differentiation and regeneration. Our transcriptional analysis reveals that Nex1 modulates a wide spectrum of genes with diverse functions, many of them being key downstream regulators of the NGF pathway, and critical to neuritogenesis, such as microtubules, microtubule-associated proteins (MAPs) and intermediate filaments. We also provide the first evidence that a basic helix-loop-helix (bHLH) protein stimulates the expression of the cyclin-dependent kinase (CDK) inhibitors belonging to the INK4 family, which plays a role in promoting cell-cycle arrest. Finally, we show a dramatic synergistic effect between Nex1 and cAMP, resulting in an impressive regeneration of an elaborate and dense neurite network. Thus, Nex1 has endowed the PC12-Nex1 cells with a distinct combination of gene products that takes part in the complex regulation of neuritogenesis and regeneration.

Animals↗
PubMed2005

Epithelial cell signaling responses to enterohemorrhagic Escherichia coli infection.

Enterohemorrhagic Escherichia coli, including the serotype O157:H7 that is most commonly identified with human disease, cause both sporadic cases and outbreaks of non-bloody diarrhea and hemorrhagic colitis. In about 10% of infected subjects, the hemolytic uremic syndrome (hemolytic anemic, thrombocytopenia, and acute renal failure) develops, likely as a consequence of systemic spread of bacterial-derived toxins variously referred to as Shiga-like toxin, Shiga toxin, and Verotoxin. Increasing evidence points to a complex interplay between bacterial products--for example, adhesins and toxins--and host signal transduction pathways in mediating responses to infection. Identification of critical signaling pathways could result in the development of novel strategies for intervention to both prevent and treat this microbial infection in humans.

Animals↗
PubMed1999

Clinical pathways.

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Critical Pathways↗