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At least 217 records · Page 12Linked to original sources
PubMed2002

Retinoic acid mediates transcriptional repression of ovine follicle-stimulating hormone receptor gene via a pleiotropic nuclear receptor response element.

The FSH receptor (FSHR) and retinoid receptors are critical regulators of gonadal function. Unlike the latter, the FSH receptors are expressed exclusively in ovarian granulosa and testicular Sertoli cells in a developmental fashion. Toward understanding the nature of various transcription factors that direct a tissue- and stage-specific expression of the FSHR gene, we have studied FP4, one of the two footprinting regions (FP3 and FP4) mapped at -241 to -269 and -284 to -303, respectively, upstream of the transcription start site of the ovine FSHR gene. Gel mobility shift assays with FP4 probe revealed two sequence-specific DNA-protein complexes in the presence of nuclear extracts from two immortal gonadal cell lines. Antibody supershift assays demonstrated that retinoic acid receptor (RAR) was involved in the complex 1 whereas steroidogenic factor-1 (SF-1) was present in the complex 2. Mutation studies revealed that DNA binding sites for RAR and SF-1 were overlapping each other within a 19-base pair length of nucleotide sequence of FP4, and a mutation in the half RAR binding site seriously affected SF-1 binding. Reporter assays showed that FP4 conferred SF-1 transactivation as well as RAR-mediated, ligand-dependent repression. Overexpression of SF-1 in a transformed Sertoli cell line partially overcame RAR-mediated suppression. For the first time, our studies reveal a direct retinoid modulation of the gonadotropin receptor promoter and suggest a mechanism by which activators and repressors compete for composite elements providing antagonistic pathways that could modulate the expression of FSHR.

Animals↗
PubMed1998

Olfactory neuroblastoma is not related to the Ewing family of tumors: absence of EWS/FLI1 gene fusion and MIC2 expression.

The relationship of olfactory neuroblastoma to the Ewing sarcoma family of tumors remains controversial due to its variable histopathology and to conflicting or inconsistent cytogenetic, immunophenotypic, and molecular data. To address this issue, we performed a morphologic, immunohistochemical, and molecular study of 20 olfactory neuroblastomas. Morphologically, the tumors consisted of nests of primitive small, round, blue cells, usually set in a background of neurofibrillary stroma. Immunohistochemical stains revealed strong reactivity for neuroendocrine markers (synaptophysin, chromogranin, neuron-specific enolase) and only focal staining for cytokeratins in two cases. Immunostaining with antibody O13 to the Ewing sarcoma-associated MIC2 antigen was uniformly negative (0 of 17). Amplifiable RNA was extracted from paraffin-embedded tissue blocks of 11 cases, and no evidence of the chimeric EWS/FLI transcript, characteristic of Ewing sarcoma, was found in any case. The EWS gene was not rearranged using Southern blot analysis in one additional case in which high molecular weight DNA was available. These results disagree with the proposed classification of olfactory neuroblastoma in the Ewing sarcoma family of tumors and suggest that therapy developed for the latter tumor group may not be biologically rational for olfactory neuroblastoma.

12E7 Antigen↗
PubMed2003

Innovations in the management of leukemia: role of biologic therapies.

Chronic myelogenous leukemia (CML) results from clonal proliferation of malignant hematologic progenitor cells and is responsible for 7% to 15% of all adult leukemias. The hallmark of CML is a genetic translocation between chromosomes 9 and 22 (the Philadelphia chromosome), which creates the abnormal bcr-abl gene and a continuously activated Bcr-Abl protein. Bcr-Abl tyrosine kinase activity leads to signal transduction and cell growth. Traditional therapies for CML include allogeneic stem cell transplantation, interferon alfa, and oral chemotherapeutic agents. However, because Bcr-Abl is the causative abnormality in CML, it represents an ideal target for rational biologic therapy. Imatinib mesylate is an orally available tyrosine kinase inhibitor that specifically blocks Bcr-Abl function. Clinical trials have demonstrated that imatinib mesylate produces rapid responses in patients with all stages of CML, including those who were resistant to interferon alfa therapy or intolerant of it. When imatinib mesylate therapy was initiated early in the course of CML, there was a complete hematologic response in 98% of the patients and a complete cytogenetic response in 72% of the patients. Although long-term safety and survival data are not yet available, imatinib mesylate is a promising new treatment option for CML that targets the molecular cause of the disease.

Antineoplastic Agents↗
PubMed2002

Intraarticular synovial sarcoma confirmed by SYT-SSX fusion transcript.

A case of intraarticular synovial sarcoma arising in the knee verified by detection of the tumor-specific SYT-SSX fusion transcript is described. Although it is extremely rare, synovial sarcoma may occur entirely within a joint space. The molecular assay for detecting a tumor-specific chimeric gene is a valuable tool for diagnosis of soft tissue sarcoma, especially for diagnostically difficult cases and tumors in unusual locations.

Artificial Gene Fusion↗
PubMed1988

A molecular analysis of doublesex, a bifunctional gene that controls both male and female sexual differentiation in Drosophila melanogaster.

The doublesex (dsx) gene regulates somatic sexual differentiation in both sexes in Drosophila melanogaster. dsx has active but opposite negative regulatory functions in males and females. In males, the dsx locus represses the genes responsible for female sexual differentiation; male differentiation functions, not being repressed, are expressed. Conversely, in females, the dsx locus represses the genes involved in male sexual differentiation and the female sexual differentiation functions, not being repressed, are expressed. We have molecularly cloned the dsx locus by chromosomal walking and localized the gene within the cloned region by determining the positions of breakpoints of chromosomal rearrangements broken in dsx and in closely flanking regions. The dsx locus is about 40 kb in size. Its DNA is unique and appears to be organized in the same way in genomes of males and females. There is a developmentally and sexually regulated set of transcripts produced by the dsx locus. During the larval period, two sex-nonspecific dsx transcripts are produced. At the end of the larval period, these transcripts disappear and are replaced by a set of male-specific and female-specific transcripts. In adults, an additional male-specific transcript appears. Because genetic analysis has shown that transcription of the dsx locus must occur during the pupal period for proper sexual differentiation, we infer that the sex-specific transcripts seen during the pupal period correspond to the sex determination regulatory functions defined by mutational analysis. The regulation of dsx expression and possible roles of the other dsx transcripts are discussed.

Animals↗
PubMed2004

Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome.

Human trisomy 21, which results in Down syndrome (DS), is one of the most complicated congenital genetic anomalies compatible with life, yet little is known about the molecular basis of DS. It is generally accepted that chromosome 21 (Chr21) transcripts are overexpressed by about 50% in cells with an extra copy of this chromosome. However, this assumption is difficult to test in humans due to limited access to tissues, and direct support for this idea is available for only a few Chr21 genes or in a limited number of tissues. The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half of the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. Here we compared the expression of 136 mouse orthologs of Chr21 genes in nine tissues of the trisomic and euploid mice. Nearly all of the 77 genes which are at dosage imbalance in Ts65Dn showed increased transcript levels in the tested tissues, providing direct support for a simple model of increased transcription proportional to the gene copy number. However, several genes escaped this rule, suggesting that they may be controlled by additional tissue-specific regulatory mechanisms revealed in the trisomic situation.

Animals↗
PubMed1998

Direct selection of conserved cDNAs from the DiGeorge critical region: isolation of a novel CDC45-like gene.

We have used a modified direct selection technique to detect transcripts that are both evolutionary conserved and developmentally expressed. The enrichment for homologous mouse cDNAs by use of human genomic DNA as template is shown to be an efficient and rapid approach for generating transcript maps. Deletions of human 22q11 are associated with several clinical syndromes, with overlapping phenotypes, for example, velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS). A large number of transcriptional units exist within the defined critical region, many of which have been identified previously by direct selection. However, no single obvious candidate gene for the VCFS/DGS phenotype has yet been found. Our technique has been applied to the DiGeorge critical region and has resulted in the isolation of a novel candidate gene, Cdc45l2, similar to yeast Cdc45p. [The sequence data described in this paper have been submitted to the EMBL data library under accession nos. AJ0223728 and AF0223729.]

Amino Acid Sequence↗
PubMed1995

Persistence of RAR alpha-PML fusion mRNA detected by reverse transcriptase polymerase chain reaction in patients in long-term remission of acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) is characterized by t(15;17), which results in the formation of two chimaeric genes, PML-RAR alpha and RAR alpha-PML. PML-RAR alpha transcripts have been detected in all cases of APL whilst those of RAR alpha-PML have been detected in only about 67% of cases. We have used reverse transcriptase polymerase chain reaction (RT-PCR) to detect both fusion transcripts serially in 18 patients in remission of APL after chemotherapy and bone marrow transplantation. All patients were negative for PML-RAR alpha, whereas in six patients (remission 3-9 years) RAR alpha-PML was consistently detected. Only one patient at remission showed the 5' breakpoint RAR alpha-PML, with the rest showing the 3' breakpoint 144 bp RAR alpha-PML. The level of sensitivity for detecting RAR alpha-PML was some 10-fold higher than that for PML-RAR alpha. Serial negative tests for PML-RAR alpha have been correlated with durable remissions, suggesting possible eradication of residual leukaemia in APL. Our results, however, show persistence of t(15;17) cells expressing RAR alpha-PML fusion mRNA in patients in long-term remission of APL. They indicate that patients considered clinically 'cured' of APL still have molecular evidence of minimal residual disease and also provide further insight into the biology of acute myeloid leukaemia.

Base Sequence↗