Microsoft Word Signalwege ausführlich doc
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- Bu səhifədəki naviqasiya:
- Targeting the Hedgehog Pathway
- Hedgehog Pathway and Metastasis
- Hedgehog Pathway and Tumor Regulation
- [edit] Evolution
- Netpath
- [edit] Data availability
- [edit] Immune signaling pathways
- [edit] Cancer signaling pathways
- [edit] Current statistics
- [edit] Community participation programme
- A Prickly Problem: Hedgehog Signaling In Hearts Blood Vessels
- See Also: Health Medicine
Signalwege – Fakultatives Material –
-Fakultativ- 23 expressed at much higher levels in the testis and mediates desert hedgehog signaling there. [19] It appears to have a distinct downstream signaling role from PTCH1. In the absence of ligand binding PTCH2 has a decreased ability to inhibit the activity of SMO. [20]
Furthermore, overexpression of PTCH2 does not replace mutated PTCH1 in basal cell carcinoma. [21]
[22] Consequently in vivo the passage of hedgehog over a receptive field that expresses the receptor leads to attenuation of the signal, an effect called ligand-dependent antagonism (LDA). In contrast to
ligands, but unlike PTCH, it has no effect on the activity of SMO. [23]
Members of the hedgehog family play key roles in a wide variety of developmental processes. [12]
One of the best studied examples is the action of Sonic hedgehog during development of the vertebrate limb. The classic experiments of Saunders and Gasseling in 1968 on the development of the chick limb bud formed the basis of the morphogen concept. They showed that identity of the digits in the chick limb was determined by a diffusible factor produced by the zone of polarizing activity (ZPA), a small region of tissue at the posterior margin of the limb. Mammalian development appeared to follow the same pattern. This diffusible factor was later shown to be Sonic hedgehog. However, precisely how SHH determines digit identity remained elusive until recently. The current model, proposed by Harfe et al., [24]
states that both the concentration and the time of exposure to SHH determines which digit the tissue will develop into in the mouse embryo (figure 6).
Digits V, IV and part of III arise directly from cells that express SHH during embryogenesis. In these cells SHH signals in an autocrine fashion and these digits develop correctly in the absence of DISP, which is required for extracellular diffusion of the ligand. These digits differ in the length of time that SHH continues to be expressed. The most posterior digit V develops from cells that express the ligand for the longest period of time. Digit IV cells express SHH for a shorter time, and digit III cells shorter still. Digit II develops from cells that are exposed to moderate concentrations of extracellular SHH. Finally, digit I development does not require SHH. It is, in a sense, the default program of limb bud cells. Hedgehog signaling remains important in the adult. Sonic hedgehog has been shown to promote the proliferation of adult stem cells from various tissues, including primitive hematopoietic cells, [25]
mammary [26]
and neural [27]
stem cells. Activation of the hedgehog pathway is required for transition of the hair follicle from the resting to the growth phase. [28] Curis Inc. together with Procter & Gamble are developing a hedgehog agonist to be used as a drug for treatment of hair growth disorders. [29]
This failed due to toxicities found in animal models. [30]
[edit] Human disease Disruption of hedgehog signaling during embryonic development, either through deleterious mutation or consumption of teratogens by the gestating mother, can lead to severe developmental abnormalities. Holoprosencephaly, the failure of the embryonic prosencephalon to divide to form cerebral hemispheres, occurs with a frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions in humans and is commonly linked to mutations in genes involved in the hedgehog pathway, including SHH and PTCH. [31]
Cyclopia, one of the most severe defects of holoprosencephaly, results if the pathway inhibitor cyclopamine is consumed by gestating mammals. [32]
Basal cell carcinoma, the most common form of cancerous malignancy, has the closest association with hedgehog signaling. Loss-of-function mutations in Patched and activating mutations in Smoothened have been identified in patients with this disease. [33] Abnormal activation of the pathway probably leads to development of disease through transformation of adult stem cells into cancer stem cells that give rise to the tumor. Cancer researchers hope that specific inhibitors of hedgehog signaling will provide an efficient therapy for a wide range of malignancies. [34]
cancers Curis and Wyeth have devised a stable hedgehog protein that can cross the blood brain barrier. [35]
In pre-clinical animal models it has shown that the pathway is up regulated upon a stroke or heart attack event. The pathway provides a protective barrier against cell death and ischemia. Agonizing the pathway this way allows the PTCH to be up regulated providing a negative feedback system. This might help minimize the side effects.
Signalwege – Fakultatives Material –
-Fakultativ- 24 The most common way to target this pathway is modulate SMO. Antagonist and agonist of SMO have already shown to effect the pathway regulation downstream. PTCH [36]
and Gli3 (5E1) [37]
antibodies are also a way to regulate the pathway. A downstream effector and strong transcriptional activator siRNA Gli1 has been used to inhibit cell growth and promote apoptosis. [38]
Hedgehog Pathway and Metastasis Activation of the Hedgehog pathway leads to an increase in Snail protein expression and a decrease in E-cadherin and Tight Junctions. [39] Hedgehog signaling also appears to be a crucial regulator of angiogenesis and thus metastasis. [40]
Hedgehog Pathway and Tumor Regulation Activation of the Hedgehog pathway leads to an increase in Angiogenic Factors (angiopoietin-1 and angiopoietin-2), [41] Cyclins (cyclin D1 and B1)), [42] anti-
apoptotic genes and a decrease in apoptotic genes (Fas). [43]
Clinical Trials GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors [2] A Study of Systemic Hedgehog Antagonist With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer[3] Video Presentation from AACR.org [4] [edit] Evolution
Figure 7. Phylogenetic relationship of hedgehog ligands (based on Ingham and McMahon, 2001). Hedgehog-like genes, 2 Patched homologs and Patched-related genes exist in the worm C. elegans. [44][45] These genes have been shown to code for proteins that have roles in C. elegans development [44]
. The hedgehog-like and Patched-related gene families are very large and function without the need for a Smoothened homolog, suggesting a distinct pattern of selection for cholesterol modification and sensing mechanisms in coelomate and pseudo-coelomate lineages [45] .
that fall within three subgroups - desert, Indian and sonic, each represented by a single mammalian gene. This is probably a consequence of the two genome duplications that occurred early in the vertebrate evolutionary history. [46] Two such events would have produced four homologous genes, one of which must have been lost. Desert hedgehogs are the most closely related to Drosophila Hh. Additional gene duplications occurred within some species [12]
such as the zebrafish Danio rerio, which has an additional tiggywinkle hedgehog gene in the sonic group. Various vertebrate lineages have adapted hedgehogs to unique developmental processes. For example, a homologue of the X.laevis banded hedgehog is involved in regeneration of the salamander limb. [47]
[48] Dorus et al. hypothesise that this allowed for more complex regulation of the protein and may have played a role in the increase in volume and complexity of the human brain.
Signalwege – Fakultatives Material –
-Fakultativ- 25 The frizzled family of WNT receptors have some sequence similarity to Smoothened. [49] However, G proteins have been difficult to link to the function Smoothened. Smoothened seems to be a functionally divergent member of the G protein coupled receptor super family. Other similarities between the WNT and Hh signaling pathways have been reviewed. [50] Nusse observed that, "a signaling system based on lipid-modified proteins and specific membrane translocators is ancient, and may have been the founder of the Wnt and Hh signaling systems". It has been suggested that invertebrate and vertebrate signaling downstream from Smoothened has diverged significantly. [51] The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to Drosophila where its role is relatively minor. Costal-2 is particularly important in Drosophila. The protein kinase Fused is a regulator of SUFU in Drosophila, but may not play a role in the Hh pathway of vertebrates. [52] In vertebrates, Hh signalling has been heavily coupled to cilia [53]
[edit] See also •
Sonic hedgehog, best studied ligand of the vertebrate pathway •
Smoothened, the conserved GPCR component of the pathway •
Cyclopamine, a small molecule inhibitor of Hh signaling [edit] External links •
http://hedgehog.sfsu.edu (Hedgehog Pathway Database) •
Netpath - A curated resource of signal transduction pathways in humans Netpath From Wikipedia, the free encyclopedia Jump to: navigation, search
[1]
is a manually curated resource of human signal transduction pathways. It is a joint effort between Pandey Lab at the Johns Hopkins University and the Institute of Bioinformatics (IOB), Bangalore, India, [2] and is also worked on by other parties. A screenshot of the homepage of NetPath. NetPath hosts 20 signaling pathways including 10 pathways with a major role in the regulation of immune system and 10 pathways with relevance to regulation of cancer.
[edit] Overview The 20 pathways contain information pertaining to protein-protein interactions, enzyme-protein substrate reactions which bring about post translational modifications (PTMs) and also a catalogue of genes which are differentially regulated upon activation of specific ligand mediated receptor pathways. The molecules which localises to different cellular organelles due to their PTMs or specific protein-protein interactions which occur downstream of ligand-receptor mediated pathway are available under translocation events. Recently, NetPath has also curated the molecules involved in the transcriptional regulation of genes in the context of immune signaling pathways. The reactions in NetPath are curated by PhD level scientists from experimental evidence available in published research articles. NetPath also contains textual description of its reactions with information on PTMs, dependence of PTMs on various signaling reactions, subcellular location, protein interaction domains or motifs and the cell type or cell line in which reactions are proved. The information in NetPath is linked to their corresponding research articles and are frequently updated. Each pathway is subjected to different level of internal quality checks and peer-review by the pathway experts and authorities.
NetPath was developed using PathBuilder, an open source software for annotating and developing pathway resources. [3] PathBuilder enables annotation of molecular events including protein-protein interactions, enzyme-substrate relationships and protein translocation events via manual or automatic methods. The features of PathBuilder include automatic validation of data formats, built-in modules for visualizing pathways, automated import of data from other pathway resources, export of data in several standard data exchange formats and an application programming interface for retrieving pathway datasets.
All the 20 pathways are freely downloadable in BioPAX, PSI-MI and SBML formats. BioPAX is an emerging standard for pathway data exchange. The pathways are made available under an adaptive Creative Commons License 2.5 which stipulates that the pathways may be used if adequate credit is given to the authors.
The following immune signaling pathways are hosted by Netpath: Signalwege – Fakultatives Material –
-Fakultativ- 26 •
B cell receptor pathway •
T cell receptor pathway •
Interleukin-1 pathway •
Interleukin-2 pathway •
Interleukin-3 pathway •
Interleukin-4 pathway •
Interleukin-5 pathway •
Interleukin-6 pathway •
Interleukin-7 pathway •
Interleukin-9 pathway [edit] Cancer signaling pathways The cancer signaling pathways were developed in collaboration with the Computational Biology Center at Memorial Sloan-ettering Cancer Center and with Bader Lab at the University of Toronto for the "Cancer Cell Map". The following cancer signaling pathways are hosted by Netpath: •
Epidermal growth factor receptor Pathway •
Transforming growth factor beta receptor pathway •
Tumor necrosis factor alpha pathway •
Alpha6 Beta4 Integrin pathway •
Inhibitor of DNA binding pathway •
Hedgehog pathway •
Notch pathway •
Wnt pathway •
Androgen receptor pathway •
Kit receptor pathway [edit] Current statistics Curated pathways 20
Molecules involved 1,682
Physical interactions 1,800
Genes transcriptionally regulated 6,582 Transport 201
Enzyme catalysis 1,218
PubMed citations 11,739
[edit] Community participation programme The community participation programme is aimed at training the students in various universities from India on curation of pathway reactions. This is a joint programme led by the Institute of Bioinformatics, Bangalore, India with active participation from Dr. Akhilesh Pandey's laboratory at the Johns Hopkins University (USA) and Gary Bader's lab at the University of Toronto, Canada. Currently, students from 3 major Indian Universities namely Pondicherry University, University of Pune and University of Mysore are participants of this community effort. J Clin Invest. 2008 Jul;118(7):2404-14. Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. Lavine KJ , Kovacs A , Ornitz DM . Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Abstract Hedgehog (HH) signaling has emerged as a critical pathway involved in the pathogenesis of a variety of tumors. As a result, HH antagonists are currently being evaluated as potential anticancer therapeutics. Conversely, activation of HH signaling in the adult heart may be beneficial, as HH agonists have been shown to increase coronary vessel density and improve coronary function after myocardial infarction. To investigate a potential homeostatic role for HH signaling in the adult heart, we ablated endogenous HH signaling in murine myocardial and perivascular smooth muscle cells. HH signaling was required for proangiogenic gene expression and maintenance of the adult coronary vasculature in mice. In the absence of HH signaling, loss of coronary blood vessels led to tissue hypoxia, cardiomyocyte cell death, heart failure, and subsequent lethality. We further showed that HH signaling specifically controlled the survival of small coronary arteries and capillaries. Together, these data demonstrate that HH signaling is essential for cardiac function at the level of the coronary vasculature and caution against the use of HH antagonists in patients with prior or ongoing heart disease. A Prickly Problem: Hedgehog Signaling In Heart's Blood Vessels ScienceDaily (June 26, 2008) — New data, generated by David Ornitz and colleagues, at Washington University School of Medicine, St. Louis, have indicated a crucial role for signaling pathways that involve the protein sonic hedgehog in maintaining the blood vessels that supply the mouse heart and keep it beating.
Signalwege – Fakultatives Material –
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Heart Disease
Vioxx
Blood Clots
Anemia
Diseases and Conditions
Immune System Reference
Human physiology
Blood pressure
Skeletal muscle
Apoptosis
These data have implications for drug development as they suggest that antagonists of hedgehog signaling pathways, such as those being developed as anticancer therapeutics, might have unwanted side effects. In the study, mice lacking the ability to mediate hedgehog signaling in cells that form part of the blood vessels that supply the heart were found to die of heart failure. This was because in the absence of hedgehog signaling the blood vessels of the heart were lost, meaning that the heart cells were no longer supplied with enough oxygen and died. Although these data indicate a need for caution when developing clinical antagonists of hedgehog signaling, it is possible that the degree of inhibition needed to have a clinical effect on tumor development might not have the effect on blood vessels of the heart that completely eliminating expression of the protein does.
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