Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is an increasing body of knowledge demonstrating that genes involved in cell fate decisions during development also play a role in the continuous cell fate decisions made by the mature immune system in response to foreign antigen. This review concentrates on the role of the Notch and Sonic hedgehog (Shh) signalling pathways in the development and function of CD4+ T lymphocytes.
Mol Immunol 2004 Jul
PMID:The Notch and Sonic hedgehog signalling pathways in immunity. 1522 6

Sonic hedgehog (SHH) is involved in the induction and differentiation of nigrostriatale dopaminergic neurons. We have investigated the promoter, two putative enhancer elements and the coding region of SHH for mutations in patients with Parkinson's disease (PD). None of the identified sequence variations were present at a significantly different frequency in PD patients compared to healthy individuals, suggesting that they are not involved in the pathogenesis of PD.
Brain Res Mol Brain Res 2004 Jul 26
PMID:Mutation analysis of the Sonic hedgehog promoter and putative enhancer elements in Parkinson's disease patients. 1524 45

EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established. To investigate the role of Edd in vivo, gene targeting was used to generate Edd knockout (Edd(Delta/Delta)) mice. While heterozygous mice had normal development and fertility, no viable Edd-deficient embryos were observed beyond E10.5, with delayed growth and development evident from E8.5 onward. Failed yolk sac and allantoic vascular development, along with defective chorioallantoic fusion, were the primary effects of Edd deficiency. These extraembryonic defects presumably compromised fetal-maternal circulation and hence efficient exchange of nutrients and oxygen between the embryo and maternal environment, leading to a general failure of embryonic cell proliferation and widespread apoptosis. Hence, Edd has an essential role in extraembryonic development.
Mol Cell Biol 2004 Aug
PMID:Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion. 1528 21

The forkhead transcription factor FOXE1 is mutated in patients with Bamforth-Lazarus syndrome that exhibit hair follicle defects, suggesting a possible role for Foxe1 in hair follicle morphogenesis. Here, we report that Foxe1 is specifically expressed in the lower undifferentiated compartment of the hair follicle, at a time and site that parallel activation of the Shh signaling pathway. The Foxe1 protein is also expressed in human and mouse basal cell carcinoma in which hedgehog signaling is constitutively activated, whereas it is undetectable in normal epidermis and squamous cell carcinoma. Moreover, expression of a dominant-negative form of Gli2 in skin results in complete suppression of Foxe1 expression in the hair follicle, whereas transcriptionally active Gli2 stimulates activity of the Foxe1 promoter. Foxe1-null skin displays aberrant hair formation with the production of thinner and curly pelage hairs. Although the hair follicle internal structure is conserved and several lineage markers are properly expressed, the orderly downgrowth of follicles is strikingly disrupted, causing disorientation, misalignment and aberrantly shaped of hair follicles. Our findings provide a strong indication that the defect in Bamforth-Lazarus syndrome is due to altered FOXE1 function in the hair follicle, and is independent of systemic defects present in affected individuals. In addition, we establish Foxe1 as a downstream target of the Shh/Gli pathway in hair follicle morphogenesis, and as a crucial player for correct hair follicle orientation into the dermis and subcutis.
Hum Mol Genet 2004 Nov 01
PMID:Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis. 1536 91

Caffeine affects early in vivo murine brain development by accelerating the evagination of the primitive neuroepithelium into telencephalic vesicles. In this model, caffeine induces the expression of the regulatory subunit alpha of protein kinase A (PKA RI alpha) and of Sonic hedgehog (Shh). The understanding of the molecular mechanisms linking caffeine and neural gene expression would benefit from a reproducible in vitro model. Accordingly, the present study aimed to determine whether caffeine modulated the expression of these genes in primary neuronal and astroglial cultures derived from developing murine neocortex. Using real-time PCR, the results showed that caffeine induced robust overexpression of Shh mRNA in both cell types without significantly modifying PKA RI alpha gene expression.
J Mol Neurosci 2004
PMID:Caffeine induces sonic hedgehog gene expression in cultured astrocytes and neurons. 1545 33

Within the adult CNS, a quiescent population of oligodendrocyte progenitor cells (OPCs) become activated in response to demyelination and give rise to remyelinating oligodendrocytes. During development, OPC differentiation is controlled by several transcription factors including Olig1 and Olig2, and Nkx2.2. We hypothesized that these genes may serve similar functions in activated adult OPCs allowing them to become remyelinating oligodendrocytes and tested this hypothesis by examining their expression during the remyelination of a toxin-induced rodent model of demyelination. During the acute phase of demyelination, OPCs within the lesion increased their expression of Nkx2.2 and Olig2, two transcription factors that in combination are critical for oligodendrocyte differentiation during developmental myelination. This activation was not associated with increases in Sonic hedgehog (Shh) expression, which does not appear essential for CNS remyelination. Consistent with a role in the activation and differentiation of OPCs, these increases were delayed in old adult animals where the rate of remyelination is slowed. Our data suggest the hypothesis that increased expression of Nkx2.2 and Olig2 plays a critically important role in the differentiation of adult OPCs into remyelinating oligodendrocytes and that these genes may present novel targets for therapeutic manipulation in cases where remyelination is impaired.
Mol Cell Neurosci 2004 Nov
PMID:Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. 1551 40

With growing amounts of genome data and constant improvement of models of molecular evolution, phylogenetic reconstruction became more reliable. However, our knowledge of the real process of molecular evolution is still limited. When enough large-sized data sets are analyzed, any subtle biases in statistical models can support incorrect topologies significantly because of the high signal-to-noise ratio. We propose a procedure to locate sequences in a multidimensional vector space (MVS), in which the geometry of the space is uniquely determined in such a way that the vectors of sequence evolution are orthogonal among different branches. In this paper, the MVS approach is developed to detect and remove biases in models of molecular evolution caused by unrecognized convergent evolution among lineages or unexpected patterns of substitutions. Biases in the estimated pairwise distances are identified as deviations (outliers) of sequence spatial vectors from the expected orthogonality. Modifications to the estimated distances are made by minimizing an index to quantify the deviations. In this way, it becomes possible to reconstruct the phylogenetic tree, taking account of possible biases in the model of molecular evolution. The efficacy of the modification procedure was verified by simulating evolution on various topologies with rate heterogeneity and convergent change. The phylogeny of placental mammals in previous analyses of large data sets has varied according to the genes being analyzed. Systematic deviations caused by convergent evolution were detected by our procedure in all representative data sets and were found to strongly affect the tree structure. However, the bias correction yielded a consistent topology among data sets. The existence of strong biases was validated by examining the sites of convergent evolution between the hedgehog and other species in mitochondrial data set. This convergent evolution explains why it has been difficult to determine the phylogenetic placement of the hedgehog in previous studies.
Mol Biol Evol 2005 Mar
PMID:Multidimensional vector space representation for convergent evolution and molecular phylogeny. 1554 50

Here we examined the role of interferon (IFN)-gamma in regulating the Sonic hedgehog (Shh) pathway and cerebellar development in bigenic mice with temporal control of IFN-gamma gene expression driven by a tetracycline-controllable promoter. In IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing bigenic or control mice, development of the cerebellum was severely affected with the persistence and extensive proliferation of the external granule neuron layer (EGL) and infiltration with modest numbers of T-lymphocytes. Following induction of IFN-gamma transgene expression, both total and tyrosine-phosphorylated signal transducer and activator of transcription (STAT)1 (the major transcriptional factor for IFN-gamma), phosphorylated STAT3 and STAT5, and expression of a number of IFN-gamma-regulated genes were significantly increased in cerebellum. In the cerebellum from IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing mice, the level of Shh and Gli-1 but not Patched (Ptch) 1 RNA was increased as was the 19-kDa signaling product of the Shh precursor protein. In situ localization studies revealed ectopic expression of the Shh gene by the granule neurons. We conclude that IFN-gamma directly affects the proliferation and fate of EGL neurons in the cerebellum by activating the Shh pathway and stimulating an autocrine growth response by these cells.
Mol Cell Neurosci 2004 Dec
PMID:Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway. 1555 26

Hedgehog (Hh) signaling regulates differentiation in numerous systems, but its functions in the control of hematopoietic differentiation have not been extensively explored. Initial studies have indicated that hedgehog signaling affects the proliferation and differentiation of erythroid progenitors (Detmer, K., et al., Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. Blood Cells Mol. Dis. 26(4) (2000) 360-372). To examine the effect of Hh signaling on the erythroid developmental program at the molecular level, Hh signaling in committed erythroid progenitors differentiating in vitro was inhibited, and the appearance/disappearance of molecular markers of erythroid differentiation was monitored. The expression timetable for CD34, CD36, the erythropoietin receptor, and glycophorin A was retarded in the absence of Hh signaling. Hemoglobinization was delayed and decreased relative to controls. Morphological changes of erythroid maturation were also delayed. The fraction of cells in S-phase was decreased during the initial period of exponential expansion as assessed by propidium iodide staining and flow cytometry, as was the rate of tritiated thymidine incorporation. A modest decrease in the proliferation rate was observed. These results suggest that Hh signaling is one of the mechanisms in the regulation of erythroid proliferation and differentiation.
Blood Cells Mol Dis
PMID:Hedgehog signaling and cell cycle control in differentiating erythroid progenitors. 1560 1

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Previously, it has been shown that Indian hedgehog (Ihh) and its two signaling receptors patched (Ptc) and smoothened (Smo) are involved in the pathogenesis of chronic pancreatitis (CP) and PDAC. In the current study we analyzed the expression, distribution, and function of another component of this signaling pathway, the human hedgehog-interacting protein (Hip), in the normal pancreas, CP and PDAC utilizing real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR), immunohistochemistry, immunofluorescence, Hip siRNA transfection, cell growth assays, and cell cycle analysis. By QRT-PCR, Hip mRNA levels were fifteenfold and fourteenfold increased in CP (n = 22) and PDAC (n = 31) tissues, respectively, compared to normal pancreatic tissues (n=20) and correlated with glioma associated antigen (Gli1) but not Ptc or Protein kinase A (PKA) mRNA levels. Only SU-8686 and BxPC-3 pancreatic cancer cells expressed Hip mRNA, whereas expression was below the level of detection in the other six pancreatic cancer cell lines tested. As shown by immunohistochemistry, Hip was expressed in normal pancreatic tissues mainly in the cytoplasm of islet cells and in smooth muscle cells of blood vessels. In contrast, in CP and PDAC there was a different distribution and staining intensity within the islets. Moreover, Hip immunoreactivity was observed in the tubular complexes, PanIN 1-3 lesions, as well as in pancreatic cancer cells. Incubation of pancreatic cancer cell lines with recombinant Hip revealed a growth inhibitory effect in SU-8686 and Capan-1 pancreatic cancer cells and no effect on cell growth in the other tested cell lines. In addition, silencing of Hip expression using specific siRNA molecules increased the growth of SU-8686 cells. In conclusion, Hip is expressed in the normal pancreas, CP and PDAC tissues. The different pattern of Hip expression and abnormal localization in the diseased pancreas suggest that the enhanced activation of hedgehog signaling in CP and PDAC is-at least in part-due to the aberrant responsiveness and expression of Hip in these diseases.
Mol Carcinog 2005 Apr
PMID:Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. 1575 13


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