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Results for “Critical Pathways”

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At least 253 records · Page 14Linked to original sources
PubMed2006

Inborn errors of development: disruption of pathways critical for normal development.

Traditionally, congenital birth defects have been classified descriptively based on the observed defects. As the genes important for some birth defects have been identified, it is clear that several of the genes mutated in malformation syndromes or genes whose expression is disrupted by environmental agents or teratogens are part of conserved signal transduction pathways. One can consider malformations to be inborn errors of development whereby pathways important for controlling development throughout evolution have been disrupted. This article focuses on three highly conserved pathways and their interactions and provides a framework that allows pediatricians to relate the phenotype of humans who have developmental disorders to the functions of genes in a signal transduction pathway.

Body Patterning↗
PubMed2001

Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma.

The formation of human malignant gliomas is thought to involve the accumulation of multiple genetic alterations. To define the function of specific alterations in glioma formation, we serially introduced genetic alterations functionally equivalent to those noted in human malignant gliomas into normal human astrocytes (NHAs). We then monitored the ability of each of these alterations to contribute to the growth of otherwise genetically stable NHAs into intracranial malignant gliomas. Using this model, we show that expression of human telomerase catalytic component (hTERT), but not E7-mediated inactivation of pRb or E6/E7-mediated inactivation of p53/pRb, was sufficient to initiate the tumorigenic process by circumventing cellular senescence in astrocytes. hTERT expression, even in combination with inactivation of p53/pRb, did not transform astrocytes. These alterations together, however, cooperated with ras pathway activation (initiated by expression of mutant H-Ras), but not with phosphatidylinositol 3-kinase pathway activation (initiated by expression of myristoylated Akt) or epidermal growth factor receptor activation, to allow for the formation of intracranial tumors strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated human grade III anaplastic astrocytomas. These results identify four pathways as key in the development of human anaplastic astrocytomas.

Animals↗
PubMed2006

The unfolded protein response: a stress signaling pathway critical for health and disease.

The endoplasmic reticulum (ER) is an intracellular organelle consisting of a membranous labyrinth network that extends throughout the cytoplasm of the cell and is contiguous with the nuclear envelope. In all eukaryotic cells, the ER is the site where folding and assembly occurs for proteins destined to the extracellular space, plasma membrane, and the exo/endocytic compartments. The ER is exquisitely sensitive to alterations in homeostasis, and provides stringent quality control systems to ensure that only correctly folded proteins transit to the Golgi and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiologic stimuli, such as perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, altered glycosylation, and overloading of cholesterol can disrupt ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved highly specific signaling pathways called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of ER stress signaling have led to major new insights into the diverse cellular and physiologic processes that are regulated by the UPR. This review summarizes the complex regulation of UPR signaling and its relevance to human physiology and disease.

Apoptosis↗
PubMed2006

Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility.

The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor beta knockout (ERbeta) mutant mice, but absent in ERalpha mutant mice. An ERalpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERalpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERalpha mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ERalpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ERalpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ERalpha-expressing neuronal afferents to GnRH neurons.

Animals↗
PubMed2005

Costimulation: critical pathways in the immunologic regulation of asthma.

T cells play an important role in the pathogenesis of allergy and asthma. T-cell receptor engagement by antigenic peptides presented to major histocompatibility complex (MHC) class II molecules and activation of costimulatory molecules are crucial in the regulation of T-cell immune responses. Costimulatory molecules are responsible for second signals that induce T-cell activation and proliferation. The best characterized costimulatory pathways include CD80/CD86 interacting with CD28, and a number of additional costimulatory molecules have recently been identified, including members of the tumor necrosis family. The positive signals induced by these molecules are counterbalanced by other members of the costimulatory family, including cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed death (PD)-1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. In this review, we describe the fundamental properties of costimulatory molecules and address the influence of costimulatory signals on allergic responses.

Antigens, CD↗
PubMed1995

Hormonal control of rat adrenal phenylethanolamine N-methyltransferase. Enzyme activity, the final critical pathway.

To examine whether glucocorticoids control rat adrenal phenylethanolamine N-methyltransferase (PNMT) through gene transcription, the effects of hypophysectomy and acute and chronic glucocorticoid replacement on PNMT mRNA and enzymatic activity were determined. Glucocorticoid depletion through hypophysectomy did not alter PNMT mRNA, whereas PNMT activity declined to approximately 25% of normal. A single dose of ACTH (4 IU SC) rapidly induced PNMT mRNA, with a six-fold peak at 6 hours postinjection. The short-term rise in PNMT mRNA was accompanied by an increase in corticosterone and elevated levels of glucocorticoid receptor mRNA. Ribosomal loading experiments suggested that available PNMT mRNA was fully utilized for protein synthesis. However, PNMT activity did not increase commensurately. Chronic ACTH treatment (4 IU SC daily for 7 days) sustained elevated levels of glucocorticoid receptor mRNA but returned corticosterone to hypophysectomized levels and decreased PNMT mRNA to 50% of normal. Despite the decline in PNMT mRNA and its partial utilization for protein synthesis, PNMT enzymatic activity was fully restored. These findings indicate that glucocorticoids exert marked but complex influences on PNMT gene transcription. In addition, corticosteroids appear to posttranscriptionally regulate PNMT protein expression, underscoring the uncoupling between the expression of PNMT mRNA and active enzyme. Thus, glucocorticoid control of gene transcription and protein synthesis do not fully account for changes in PNMT expression, consistent with the previous observation that glucocorticoid control of PNMT proteolysis is also important in PNMT regulation and the potential for epinephrine biosynthesis.

Adrenal Glands↗
PubMed2006

Critical pathways in heart function: bis(2-chloroethoxy)methane-induced heart gene transcript change in F344 rats.

Gene transcript changes after exposure to the heart toxin, bis(2-chloroethoxy)methane (CEM), were analyzed to elucidate mechanisms in cardiotoxicity and recovery. CEM was administered to 5-week-old male F344/N rats at 0, 200, 400, or 600 mg/kg by dermal exposure, 5 days per week, for a total of 12 doses by study day 16. Heart toxicity occurred after 2 days of dosing in all 3 regions of the heart (atrium, ventricle, interventricular septum) and was characterized by myofiber vacuolation, necrosis, mononuclear-cell infiltration, and atrial thrombosis. Ultrastructural analysis revealed that the primary site of damage was the mitochondrion. By day 5, even though dosing was continued, the toxic lesions in the heart began to resolve, and by study day 16, the heart appeared histologically normal. RNA was extracted from whole hearts after 2 or 5 days of CEM dosing. After a screen for transcript change by microarray analysis, dose-response trends for selected transcripts were analyzed by qRT-PCR. The selected transcripts code for proteins involved in energy production, control of calcium levels, and maintenance of heart function. The down-regulation of ATP subunit transcripts (Atp5j, ATP5k), which reside in the mitochondrial membranes, indicated a decrease in energy supply at day 2 and day 5. This was accompanied by down-regulation of transcripts involved in high-energy consumption processes such as membrane transport and ion channel transcripts (e.g., abc1a, kcnj12). The up-regulation of transcripts encoding for temperature regulation and calcium binding proteins (ucp1 and calb3) only at the 2 low exposure levels, suggest that these adaptive processes cannot occur in association with severe cardiotoxicity as seen in hearts at the high exposure level. Transcript expression changes occurred within 2 days of CEM exposure, and were dose-and time-dependent. The heart transcript changes suggest that CEM cardiotoxicity activates protective processes associated energy conservation and maintenance of heart function.

Animals↗
PubMed2006

Common critical pathways in embryogenesis and cancer.

Cancer may arise because the developmental programs that create the dramatic alterations in form and structure in embryonic development are potentially corrupted. The cells in our bodies retain memories of these processes and cancer can occur later in life if imperfections occur in the fidelity of these pathways. This article is particularly interested in the phenomenon of epithelial to mesenchymal transition, which occurs in embryogenesis. Also reviewed are the small molecules and pathways that are involved both in homeostasis in adult epithelium and embryogenesis in utero. There are five such pathways in particular selected for review in this article: the Wnt pathway, Hedgehog, Notch, PAR and Bone morphogenetic peptide/TGF beta. These are usually conserved throughout mammalian evolution. Though they have been arbitrarily separated in this article they are not exclusive from one another. Their pathologically altered expression is found especially frequently in childhood tumours where they may recapitulate their developmental role, and in tumours that resemble primitive precursor cells. These pathways are important for selecting cell fates, cellular rearrangements, cytological context and morphologic design in embryology as well as participating in epithelial function in adults.

Animals↗