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Sissy M Jhiang - One of the best experts on this subject based on the ideXlab platform.
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forskolin 8 br 3 5 cyclic adenosine 5 monophosphate and catalytic protein kinase a expression in the nucleus increase radioiodide uptake and sodium iodide symporter protein levels in ret Ptc1 expressing cells
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Anjli Venkateswaran, Derek K Marsee, Steven H Green, Sissy M JhiangAbstract:RET/Ptc1, a thyroid-specific oncogene, has been reported to down-regulate sodium/iodide symporter (NIS) expression and function in vitro and in vivo. Recently, RET/Ptc1 has been shown to interfere with TSH signaling at multiple levels in thyroid cells. The objective of this study was to investigate whether RET/Ptc1-mediated NIS reduction can be rescued by activating cAMP-protein kinase A (PKA) pathways. We showed that both forskolin and 8-Br-cAMP increase radioiodide uptake and NIS protein in RET/Ptc1-expressing cells to the same extent as the parental PC Cl 3 cells. We found that RET/Ptc1 decreases nuclear localization of catalytic PKA, and forskolin treatment was able to counteract this RET/Ptc1 effect. Furthermore, transient expression of catalytic PKA in the nucleus increased radioiodide uptake and NIS protein in RET/Ptc1-expressing cells. Taken together, these studies suggest that RET/Ptc1 down-regulates NIS expression by interrupting TSH/cAMP signaling, and this RET/Ptc1 effect can be reversed by ac...
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inhibition of heat shock protein 90 a novel ret Ptc1 associated protein increases radioiodide accumulation in thyroid cells
Journal of Biological Chemistry, 2004Co-Authors: Derek K Marsee, Anjli Venkateswaran, Douangsone D Vadysirisack, Zhaoxia Zhang, Dale D Vandre, Sissy M JhiangAbstract:Abstract RET/Ptc1 is a rearranged form of the RET tyrosine kinase commonly seen in papillary thyroid carcinomas. It has been shown that RET/Ptc1 decreases expression of the sodium/iodide symporter (NIS), the molecule that mediates radioiodide therapy for thyroid cancer. Using proteomic analysis, we identify hsp90 and its co-chaperone p50cdc37 as novel proteins associated with RET/Ptc1. Inhibition of hsp90 function with 17-allylamino-17-demothoxygeldanamycin (17-AAG) reduces RET/Ptc1 protein levels. Furthermore, 17-AAG increases radioiodide accumulation in thyroid cells, mediated in part through a protein kinase A-independent mechanism. We show that 17-AAG does not increase the total amount of NIS protein or cell surface NIS localization. Instead, 17-AAG increases radioiodide accumulation by decreasing iodide efflux. Finally, the ability of 17-AAG to increase radioiodide accumulation is not restricted to thyroid cells expressing RET/Ptc1. These findings suggest that 17-AAG may be useful as a chemotherapeutic agent, not only to inhibit proliferation but also to increase the efficacy of radioiodide therapy in patients with thyroid cancer.
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loss of p53 promotes anaplasia and local invasion in ret Ptc1 induced thyroid carcinomas
American Journal of Pathology, 2000Co-Authors: Krista M D La Perle, Sissy M Jhiang, Charles C CapenAbstract:Papillary thyroid carcinomas in humans are associated with the ret /PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret /Ptc1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53−/− mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret /Ptc1-induced thyroid tumors. The majority of p53−/− mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret /Ptc1 mice developed thyroid carcinomas, but tumors in p53−/− mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/− mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/− mice ≤28 weeks of age or p53−/− mice ≤ 17 weeks of age; however, an older (170-day-old) male p53−/− mouse used to maintain the colony developed anaplastic thyroid carcinoma with liver metastases. These findings demonstrate that the lack of functional p53 in ret /Ptc1 mice promotes anaplasia and invasiveness of thyroid carcinomas.
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a novel multicolor hybridization scheme applied to localization of a transcribed sequence d10s170 h4 and deletion mapping in the thyroid cancer cell line tpc 1
Cytogenetic and Genome Research, 1996Co-Authors: Gregg H Jossart, B Obrien, J F Cheng, Q Tong, Sissy M Jhiang, O H Clark, Heinzulrich G WeierAbstract:The sequence-tagged site (STS) D10S170, also referred to as H4, is a gene of unknown function. Its 5’ end was found fused to the catalytic domain of the RET protooncogene to generate RET/Ptc1, the mos
Massimo Santoro - One of the best experts on this subject based on the ideXlab platform.
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ccdc6 represses creb1 activity by recruiting histone deacetylase 1 and protein phosphatase 1
Oncogene, 2010Co-Authors: Vincenza Leone, Massimo Santoro, Gelsomina Mansueto, Giovanna Maria Pierantoni, Mara Tornincasa, Francesco Merolla, Aniello Cerrato, M Grieco, Andrea Scaloni, Angela CelettiAbstract:RET/papillary thyroid carcinoma 1 (Ptc1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/Ptc1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/Ptc1 activation.
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efficient inhibition of ret papillary thyroid carcinoma oncogenic kinases by 4 amino 5 4 chloro phenyl 7 t butyl pyrazolo 3 4 d pyrimidine pp2
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Francesca Carlomagno, Donata Vitagliano, Teresa Guida, Fulvio Basolo, Maria Domenica Castellone, Rosa Marina Melillo, Alfredo Fusco, Massimo SantoroAbstract:Inappropriate activation of the RET receptor tyrosine kinase causes development of papillary and medullary thyroid cancer. We have previously shown that pyrazolopyrimidine is a potent inhibitor of the RET kinase. Here, we show that 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) (PP2), another pyrazolopyrimidine, blocks the enzymatic activity of the isolated RET kinase and RET/Ptc1 oncoprotein at IC50 in the nanomolar range. PP2 blocked in vivo phosphorylation and signaling of the RET/Ptc1 oncoprotein. PP2 prevented serum-independent growth of RET/Ptc1-transformed NIH3T3 fibroblasts and of TPC1 and FB2, two human papillary thyroid carcinoma cell lines that carry spontaneous RET/Ptc1 rearrangements. Finally, PP2 blocked invasion of type I collagen matrix by TPC1 cells. Thus, pyrazolopirimidines hold promise for the treatment of human cancers sustaining oncogenic activation of RET.
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ret Ptc1 oncogene signaling in pc cl 3 thyroid cells requires the small gtp binding protein rho
Oncogene, 2001Co-Authors: Maria Vittoria Barone, Maria Domenica Castellone, Rosa Marina Melillo, Alfredo Fusco, Leandra Sepe, Alba Mineo, Giovanni Santelli, Carmen Monaco, Donatella Tramontano, Massimo SantoroAbstract:RET/Ptc1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho
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expression of the ret ptc fusion gene as a marker for papillary carcinoma in hashimoto s thyroiditis
Laryngoscope, 1997Co-Authors: Ari Wirtschafter, Alfredo Fusco, Massimo Santoro, Richard R Schmidt, David Rosen, Nandita Kundu, Hinke A B Multhaupt, Joseph P Atkins, Marc Rosen, William M KeaneAbstract:Hashimoto's thyroiditis is an inflammatory disease of the thyroid gland with autoimmune etiology. 1 Patients afflicted with Hashimoto's have a higher risk of thyroid malignancies such as papillary thyroid carcinoma. 2 In the present study, we investigated the frequency of papillary thyroid carcinoma specific genes in patients diagnosed with Hashimoto's disease. The newly identified oncogenes RET/Ptc1 and RET/PTC3 provide useful and specific markers of the early stages of papillary carcinoma as they are highly specific for malignant cells. Using a sensitive and specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we found messenger RNA (mRNA) expression for the RET/Ptc1 and RET/PTC3 oncogenes in 95% of the Hashimoto's patients studied. All Hashimoto's patients presenting without histopathologic evidence of papillary thyroid cancer showed molecular genetic evidence of cancer. These data suggest that multiple, independent occult tumors exist in these patiens at high frequency.
Matthew P Scott - One of the best experts on this subject based on the ideXlab platform.
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Insulin-like Growth Factor 2 is Required for Progression to Advanced Medulloblastoma in patched1 Heterozygous Mice
2015Co-Authors: Ryan B. Corcoran, Tal Raveh, Monique T. Barakat, Eunice Y. Lee, Matthew P ScottAbstract:Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNPs), the precursor cells of MB. Mutations in the Shh receptor gene, patched1 (Ptc1+/-), lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for Ptc1+/- shows distinct steps of progression. Most Ptc1+/- mice form clusters of pre-neoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In ∼15 % of mice, these pre-neoplastic cells will become fast-growing, lethal tumors. It was previously shown (1) that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in Ptc1+/- mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of pre-neoplastic lesions, but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNPs) and a MB cell line, PZp53MED. Blocking igf2 signaling inhibited growth of PZp53MED cells, implicating igf2 as a potential clinical target
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patched1 regulates hedgehog signaling at the primary cilium
Science, 2007Co-Authors: Rajat Rohatgi, Ljiljana Milenkovic, Matthew P ScottAbstract:Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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differential requirement for gli2 and gli3 in ventral neural cell fate specification
Developmental Biology, 2003Co-Authors: Jun Motoyama, Ljiljana Milenkovic, Mizuho Iwama, Yayoi Shikata, Matthew P ScottAbstract:Sonic hedgehog (Shh) directs the development of ventral cell fates, including floor plate and V3 interneurons, in the mouse neural tube. Here, we show that the transcription factors Gli2 and Gli3, mediators of Shh signaling, are required for the development of the ventral cell fates but make distinct contributions to controlling cell fates at different locations along the rostral–caudal axis. Mutants lacking Patched1 (Ptc1), the putative receptor of Shh, were used to analyze Gli functions. Ptc1−/− mutants develop floor plate, motor neuron, and V3 interneuron progenitors in lateral and dorsal regions, suggesting that the normal role of Ptc1 is to suppress ventral cell development in dorsal neural tube. The Ptc1−/− phenotype is rescued, with restoration of dorsal cell types, by the lack of Gli2, but only in the caudal neural tube. In triple mutants of Gli2, Gli3, and Ptc1, dorsal and lateral cell fates are restored in the entire neural tube. These observations suggest that Gli2 is essential for ventral specification in the caudal neural tube, and that in more rostral regions, only Gli3 can promote development of ventral cells if Gli2 is absent. Thus, Shh signaling is mediated by overlapping but distinct functions of Gli2 and Gli3, and their relative contributions vary along the rostral–caudal axis.
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a mouse model for medulloblastoma and basal cell nevus syndrome
Journal of Neuro-oncology, 2001Co-Authors: Ryan B. Corcoran, Matthew P ScottAbstract:Medulloblastoma (MB), a tumor of the cerebellum, is the most frequent type of malignant childhood brain tumor. Multiple genes are causally involved in medulloblastoma including PATCHED1 (PTCH). The Patched1 (Ptc1) protein is a receptor for Sonic hedgehog (Shh), a secreted protein ligand. Shh is involved in many signaling processes that control cell fate and growth, among which is its emission from Purkinje cells in the developing cerebellum. Purkinje cell-derived Shh stimulates mitosis of the granule cell precursors that may be the cell type of origin in medulloblastoma. Ptc1 limits the effects of the Shh signal, so mutations in PTCH may lead to persistent granule cell precursors susceptible to further genetic or environmental events that cause medulloblastoma. Mice heterozygous for patched1 (Ptc1) mutations, like heterozygous PTCH humans, have a high rate of medulloblastoma as well as other tumors. We discuss features of the mouse model and how it is contributing to understanding the process of brain tumorigenesis.
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the developmental biology of brain tumors
Annual Review of Neuroscience, 2001Co-Authors: Robert J Wechslerreya, Matthew P ScottAbstract:▪ Abstract Tumors of the central nervous system (CNS) can be devastating because they often affect children, are difficult to treat, and frequently cause mental impairment or death. New insights into the causes and potential treatment of CNS tumors have come from discovering connections with genes that control cell growth, differentiation, and death during normal development. Links between tumorigenesis and normal development are illustrated by three common CNS tumors: retinoblastoma, glioblastoma, and medulloblastoma. For example, the retinoblastoma (Rb) tumor suppressor protein is crucial for control of normal neuronal differentiation and apoptosis. Excessive activity of the epidermal growth factor receptor and loss of the phosphatase PTEN are associated with glioblastoma, and both genes are required for normal growth and development. The membrane protein Patched1 (Ptc1), which controls cell fate in many tissues, regulates cell growth in the cerebellum, and reduced Ptc1 function contributes to medullobl...
James Mapes - One of the best experts on this subject based on the ideXlab platform.
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nbp2 targets the Ptc1 type 2c ser thr phosphatase to the hog mapk pathway
The EMBO Journal, 2004Co-Authors: James MapesAbstract:The yeast high osmolarity glycerol (HOG) pathway signals via the Pbs2 MEK and the Hog1 MAPK, whose activity requires phosphorylation of Thr and Tyr in the activation loop. The Ptc1-type 2C Ser/Thr phosphatase (PP2C) inactivates Hog1 by dephosphorylating phospho-Thr, while the Ptp2 and Ptp3 protein tyrosine phosphatases dephosphorylate phospho-Tyr. In this work, we show that the SH3 domain-containing protein Nbp2 negatively regulates Hog1 by recruiting Ptc1 to the Pbs2-Hog1 complex. Consistent with this role, NBP2 acted as a negative regulator similar to Ptc1 in phenotypic assays. Biochemical analysis showed that Nbp2, like Ptc1, was required to inactivate Hog1 during adaptation. As predicted for an adapter, deletion of NBP2 disrupted Ptc1-Pbs2 complex formation. Furthermore, Nbp2 contained separate binding sites for Ptc1 and Pbs2: the novel N-terminal domain bound Ptc1, while the SH3 domain bound Pbs2. In addition, the Pbs2 scaffold bound the Nbp2 SH3 via a Pro-rich motif distinct from that which binds the SH3 domain of the positive regulator Sho1. Thus, Nbp2 recruits Ptc1 to Pbs2, a scaffold for both negative and positive regulators.
Irene Ota - One of the best experts on this subject based on the ideXlab platform.
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Ptc1 a type 2c ser thr phosphatase inactivates the hog pathway by dephosphorylating the mitogen activated protein kinase hog1
Molecular and Cellular Biology, 2001Co-Authors: Janel Warmka, Jennifer Hanneman, Ji Lee, Dipesh S Amin, Irene OtaAbstract:The HOG (high-osmolarity glycerol) mitogen-activated protein kinase (MAPK) pathway regulates the osmotic stress response in the yeast Saccharomyces cerevisiae. Three type 2C Ser/Thr phosphatases (PTCs), Ptc1, Ptc2, and Ptc3, have been isolated as negative regulators of this pathway. Previously, multicopy expression of Ptc1 and PTC3 was shown to suppress lethality of the sln1Delta strain due to hyperactivation of the HOG pathway. In this work, we show that PTC2 also suppresses sln1Delta lethality. Furthermore, the phosphatase activity of these PTCs was needed for suppression, as mutation of a conserved Asp residue, likely to coordinate a metal ion, inactivated PTCs. Further analysis of Ptc1 function in vivo showed that it inactivates the MAPK, Hog1, but not the MEK, Pbs2. In the wild type, Hog1 kinase activity increased transiently, approximately 12-fold in response to osmotic stress, while overexpression of Ptc1 limited activation to approximately 3-fold. In contrast, overexpression of Ptc1 did not inhibit phosphorylation of Hog1 Tyr in the phosphorylation lip, suggesting that Ptc1 does not act on Pbs2. Deletion of Ptc1 also strongly affected Hog1, leading to high basal Hog1 activity and sustained Hog1 activity in response to osmotic stress, the latter being consistent with a role for Ptc1 in adaptation. In vitro, Ptc1 but not the metal binding site mutant, Ptc1D58N, inactivated Hog1 by dephosphorylating the phosphothreonine but not the phosphotyrosine residue in the phosphorylation lip. Consistent with its role as a negative regulator of Hog1, which accumulates in the nucleus upon activation, Ptc1 was found in both the nucleus and the cytoplasm. Thus, one function of Ptc1 is to inactivate Hog1.