Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small round cell tumors of childhood can be histologically ambiguous, can require tumor markers for an accurate diagnosis, and include neuroblastoma, peripheral primitive neuroectodermal tumor (pPNET), Ewing's sarcoma (ES), lymphoma, and rhabdomyosarcoma. Because the cell type of origin for ES remains controversial, characterizing gene expression in ES can provide diagnostic markers and lead to better understanding of tumor biology. We studied RNA expression of the neuronal genes protein gene product 9.5 (PGP 9.5) and tyrosine hydroxylase (TH) by Northern analysis in cell lines and tissue from small round cell tumors. PGP 9.5 showed strong expression in 17 of 17 neuroblastoma cell lines, 9 of 9 pPNET cell lines, and 11 of 11 ES cell lines. PGP 9.5 was weakly expressed in 1 of 1 alveolar rhabdomyosarcoma cell lines but not in 1 of 1 embryonal rhabdomyosarcomas, and weak expression was seen in 1 of 7 leukemia cell lines. In tumor tissue, all 12 neuroblastomas expressed PGP 9.5, as did all 7 pPNET and all 7 ES. PGP 9.5 was very weakly expressed in 6 of 9 rhabdomyosarcomas and 1 of 9 lymphomas. TH was expressed only in neuroblastomas, and no TH expression was seen in cell lines or tissue from other tumors. As high expression of PGP 9.5 was only found in neural tumors; PGP 9.5 expression by ES provides further evidence for a neural origin of this tumor, whereas TH expression is highly specific for neuroblastomas. PGP 9.5 expression should allow sensitive detection of minimal residual disease for ES and pPNET using reverse transcription-PCR, and the variability in TH and PGP 9.5 expression levels in neuroblastomas indicates that expression of both genes should be used for monitoring minimal residual disease by reverse transcription-PCR.
Clin Cancer Res 2000 Feb
PMID:Expression of protein gene product 9.5 and tyrosine hydroxylase in childhood small round cell tumors. 1069 May 38

We have used the rat tyrosine hydroxylase promotor to overexpress MYCN in the neural crest of transgenic mice, resulting in a mouse model for neuroblastoma. Using PCR analysis of microsatellite markers, we conducted a genome-wide analysis in tumors from these animals. Regions of chromosomes 1, 3, 10, 11, 14, and 18 were affected in 20-50% of tumors. Analysis of a subset of these tumors by comparative genomic hybridization was consistent with the microsatellite data. The changes on mouse chromosomes 1, 11, 14, and 18 were syntenic with corresponding regions of loss of heterozygosity in human neuroblastoma, suggesting that genes implicated in the mouse tumors may also play a role in the pathogenesis of the human disease. One-third of the mouse tumors shared abnormalities on chromosomes 1, 3, and 10, whereas the remainder of tumors did not show this combination. These data suggest that genetic mutations on chromosomes 1, 3, and 10 cooperate in the pathogenesis of neuroblastoma and that neuroblastoma in the mouse arises from at least two distinct genetic pathways, one of which is dependent on lesions in chromosomes 1, 3, and 10, the other of which is not.
Cancer Res 2000 May 01
PMID:Genome-wide screen for allelic imbalance in a mouse model for neuroblastoma. 1081 Nov 28

Neuroblastoma originates from neural crest cells and is the most common extracranial solid tumor in childhood. Bone metastasis in neuroblastoma is an unfavorable prognostic factor even with intensive therapy. In the present study, we screened four cell lines of human neuroblastoma (NB-1, NB-16, NB-19, and NH-6) for tumorigenicity and metastatic capacity in nude mice and found that NB-19 cells caused osteolytic lesions after s.c. injection into mice. To detect micrometastases in the host tissue, we performed two kinds of PCR-based metastasis assays: (a) genomic PCR assay using the primers for human genome-specific Alu sequence; and (b) reverse transcription-nested PCR assay that detects the expression of tyrosine hydroxylase, a marker specific for neuroblastoma. The results of these PCR assays revealed the colonization of human neuroblastoma cells in the bone marrow of the mice that had received the s.c. injection of NB-19 cells. Because osteoclastic bone resorption has been reported to play important roles in osteolysis in some cancers such as breast cancer, we next examined the osteoclast (OC)-inducing activity of NB-19 cells using a coculture system in which NB-19 cells were cultured with murine bone marrow cells containing OC precursors and stromal cells. NB-19 cells induced tartrate-resistant acid phosphatase-positive multinucleated OC-like cells without requirement of 1,25-dihydroxyvitamin D3 or other osteoclastogenic stimulators. To investigate the factors involved in the osteoclastogenesis in the coculture of mouse marrow cells and NB-19 cells, we performed reverse transcription-PCR analysis and revealed the increased expression of receptor activator of nuclear factor kappaB ligand (RANKL) in the coculture compared with the culture of bone marrow cells alone. Interleukin-1alpha and cyclooxygenase-2 expression in the murine marrow cells was also increased in the presence of NB-19 cells. To further study the role of RANKL in the OC-like cell formation in the coculture of NB-19 cells and murine marrow cells, an expression vector encoding the active portion of the murine osteoprotegerin, which is the native inhibitor of RANKL action, was constructed and introduced into COS-7 cells. The conditioned media of the COS-7 cells transfected with the osteoprotegerin expression vector effectively blocked OC-like cell formation in the coculture of the bone marrow cells and NB-19 cells. These results suggested that in the bone microenvironment of NB-19-bearing mice, the stimulated expression of RANKL plays an important role in OC formation, leading to osteolytic bone metastasis.
Cancer Res 2001 Feb 15
PMID:Receptor activator of nuclear factor kappaB ligand (RANKL) is a key molecule of osteoclast formation for bone metastasis in a newly developed model of human neuroblastoma. 1124 77

Tumor cells that contaminate hematopoietic cell preparations contribute to the relapse of neuroblastoma patients who receive autologous stem cell rescue as a component of therapy. Therefore, effective purging methods are needed. This study details in vitro experiments to develop a viral-directed enzyme prodrug purging method that specifically targets neuroblastoma cells. The approach uses an adenovirus to deliver the cDNA encoding a rabbit liver carboxylesterase that efficiently activates the prodrug irinotecan,7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11). The data show that an adenoviral multiplicity of infection of 50 transduces 100% of cultured neuroblastoma cells and primary tumor cells, irrespective of the level of tumor cell line contamination. Exposure of neuroblastoma cell lines or of mixtures of these cell lines with CD34(+) cells at a ratio of 10:90 to replication-deficient AdRSVrCE for 24 h and subsequent exposure of cells to 1-5 microM CPT-11 for 4 h increased the toxicity of CPT-11 to three neuroblastoma cell lines (SJNB-1, NB-1691, and SK-N-SH) from approximately 20-50-fold and eradicated their clonogenic potential. Also, after "purging," RNA for neuroblastoma cell markers (tyrosine hydroxylase, synaptophysin, and N-MYC) was undetectable by reverse transcription-PCR. In contrast, the purging protocol did not affect the number or type of colonies formed by CD34(+) cells in an in vitro progenitor cell assay. No bystander effect on CD34(+) cells was observed. The method described is being investigated for its potential clinical utility, particularly its efficacy for use with patients having relatively high tumor burdens, because no published methods have been shown to be efficacious when the tumor burden exceeds 1%.
Cancer Res 2001 Jul 01
PMID:A virus-directed enzyme prodrug therapy approach to purging neuroblastoma cells from hematopoietic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. 1143 45

1. In depression, psychiatric symptoms are frequently associated with impaired cardiovascular function and perhaps also increased risk for cancer diseases. Pathophysiological basis of this comorbidity is not clearly understood. Molecular events involved, particularly factors modified by chronic stress exposure, may only be evaluated in animal models of depression. 2. Present experiments were aimed to study parameters related to cardiovascular system (tyrosine hydroxylase (TH) gene expression in adrenal glands) and carcinogenesis (retinoic acid receptors in the liver) in the chronic mild stress model of depression. 3. Chronic mild stress induced a rise in adrenal TH gene expression in both male and female rats. Gender dependent changes were found in retinoic acid receptor binding with stress-induced activation in females but not males. Ovariectomized animals exhibited higher retinoic acid receptor binding. slightly elevated TH mRNA levels and failed to respond to chronic mild stress exposure with further increase in TH mRNA levels. Similarly, chronic mild stress induced an anhedonic state manifested by decreased sucrose preference in control but not ovariectomized rats. 4. Presented data document that central neurochemical and behavioral changes in animals exposed to chronic mild stress model of depression are associated with changes in adrenal TH gene expression and with gender dependent changes in retinoic acid receptor status in the liver. Such alterations may participate in the development of pathological changes and could participate on increased risk for cardiovascular and oncologic comorbidity in depressive patients.
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PMID:Altered function of peripheral organ systems in rats exposed to chronic mild stress model of depression. 1177 69

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

Alteration in ganglioside composition in F-11 cells by suppression of GD3-synthase gene expression resulted in greatly reduced tumor growth and metastasis when the cells were injected into nude mice. To identify genes whose expression is correlated with the decreased level of ganglioside GD3, we analyzed gene expression profiles of the GD3-suppressed F-11 cells and the control F-11 cells using DNA microarrays. We identified a set of GD3-related genes, most of which are involved in tumor growth and development. The genes that define the proliferation-transformation signature are down-regulated, such as creatine kinase-B (CKB), upstream stimulation factor 1 (USF-1), type II cAMP-dependent protein kinase regulatory subunit (RII PKA), and tyrosine hydroxylase (TH). On the other hand, the genes that define the differentiation-reverse transformation signature are up-regulated, including p160 myb-binding protein (P160), brain factor-2, insulin-like growth factor-binding protein (IGFBP), and growth/differentiation factor 11. Transcriptional levels of the genes that showed the most distinct GD3-related expression change were validated by reverse transcription-polymerase chain reaction (RT-PCR). Defining GD3-related genes may lead to identification of clinically relevant therapeutics and to understanding of the mechanism(s) by which ganglioside GD3 affects tumor growth and metastasis.
Cancer Lett 2002 Apr 08
PMID:Variations in gene expression patterns correlated with phenotype of F-11 tumor cells whose expression of GD3-synthase is suppressed. 1184 46

Loss of von Hippel-Lindau (VHL) gene function leads to VHL disease, which is characterized by vascular tumors of the central nervous system, renal clear cell carcinomas, and pheochromocytomas. Pheochromocytomas express high levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. PC12 cells that express VHL antisense RNA had 5-10-fold reduced levels of endogenous pVHL and 2-3-fold increased levels of TH protein and mRNA. Nuclear run-on analysis revealed an augmentation of TH gene transcription with enhanced efficiency of transcript elongation in the 3' region of the gene. Transient coexpression of the VHL antisense RNA with a TH promoter reporter construct increased TH promoter activity by 2-3-fold. A decrease in pVHL accumulation also resulted in an increase in TH mRNA accumulation and transcription of the TH gene during hypoxia. This is the first evidence that endogenous pVHL is a physiological regulator of the catecholaminergic phenotype. Thus, loss of pVHL function may be causative in pheochromocytoma-associated hypercatecholaminemia and arterial hypertension.
Cancer Res 2002 Mar 15
PMID:Endogenous von Hippel-Lindau tumor suppressor protein regulates catecholaminergic phenotype in PC12 cells. 1191 40

Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
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PMID:Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. 1201 61

Autologous stem cell transplantation is used to rescue cancer patients from myelosuppression caused by high-dose chemotherapy. However, autologous grafts often contain tumor cells that can contribute directly to relapse. Current purging methods are useful when fewer than 1% tumor cells contaminate the bone marrow, and patients with tumor burdens of >1% are considered ineligible for chemotherapy that necessitates stem cell rescue. Using neuroblastoma (NB) as a model system, we developed a method that is effective even with tumor burdens of 10-25%. Mixtures of NB-1691 NB cells and CD34(+) hematopoietic cells purged by this method showed no evidence of viable tumor cells as assessed by clonogenic assays or reverse transcription-PCR for the NB cell markers tyrosine hydroxylase and N-MYC. The efficacy and lack of toxicity of the method were verified using in vivo mouse models. Severe combined immunodeficient mice that received purged cell preparations containing 10% NB-1691 cells survived without evidence of disease for the observation period (>1 year), whereas mice that received unpurged cells developed disseminated disease requiring euthanasia 73-96 days after injection of cells. No evidence of toxicity to the mice was detected by numerous laboratory values for bone marrow, liver, and kidney function, and no difference was seen in the ability of purged cell mixtures versus unmanipulated CD34(+) cells to reconstitute the marrow of non-obese diabetic severe combined immunodeficient mice. In a pilot study, marrow was obtained from eight patients who had >/=1% metastatic tumor burden. All eight samples were purged to the level of detection by reverse transcription-PCR (samples from seven patients) or clonogenic potential (sample from one patient), whichever assay was used. The described adenovirus/rabbit carboxylesterase/CPT-11 (irinotecan, 7-ethyl-10[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) virus-directed enzyme prodrug method may be useful for patients whose tumor burdens exceed 1% at the time of stem cell harvest. Assessment of purging efficacy with additional samples from NB patients is ongoing.
Cancer Res 2002 Sep 01
PMID:Efficacy and toxicity of a virus-directed enzyme prodrug therapy purging method: preclinical assessment and application to bone marrow samples from neuroblastoma patients. 1220 53


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