Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytogenetic and molecular studies in neuroblastoma suggest the presence of a tumor suppressor gene at the distal band p36 of human chromosome 1. We described a constitutional translocation t(1;17)(p36;q12-q21), involving the critical region 1p36, in a patient with neuroblastoma, and hypothesized that the translocation predisposed the patient to tumor development. Here we report the molecular delineation of the translocation breakpoints. Somatic cell hybrids were generated by fusion of the patient's fibroblasts with the thymidine kinase deficient hamster cell line, a3. In hybrid cell lines which retained the human derivative chromosomes, the position of chromosome 1p and 17q DNA probes respective to the translocation breakpoints was determined by fluorescence in situ hybridization and Southern blot analysis. The chromosome 1p breakpoint was localized within a repetitive region encoding t-RNA genes, with 12A-2 (PND) as most distal and pHE2.6 (A12M2) as most proximal single-copy breakpoint flanking markers. For the chromosome 17 breakpoint, the proximal and distal flanking markers were identified as 7G4 (NF1) and cMCP-3 (SCYA7), respectively. In this study, cMCP-3 (SCYA7), encoding the human monocyte chemotactic protein-3, was mapped between NF1 and ERBB2. As a pivotal step towards breakpoint cloning, at present these flanking markers optimally delineate the breakpoint regions of both chromosomes 1 and 17 at the molecular level.
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PMID:Constitutional translocation t(1;17)(p36.31-p36.13;q11.2-q12.1) in a neuroblastoma patient. Establishment of somatic cell hybrids and identification of PND/A12M2 on chromosome 1 and NF1/SCYA7 on chromosome 17 as breakpoint flanking single copy markers. 770 Jun 33

Neuroblastoma is a childhood cancer which originates in the embryonic tissue of the developing sympathetic neural crest. In 1972, Dr. A. Knudson hypothesised a similar 'two-hit mutation' model for the origin of neuroblastoma as for retinoblastoma and Wilms tumor. In this model, malignant cell growth is caused by mutations of both alleles of a tumor suppressor gene. In hereditary tumors, a germinal mutation is present in all cells of the individual, a mutation of the remaining allele by a somatic hit causes loss of gene function. Sporadic tumors result from two somatic mutations of a tumor suppressor gene involving both alleles within the same cell. The occurrence of patients with a constitutional chromosomal deletion syndrome in association with tumor facilitated the cloning of a retinoblastoma gene and of a Wilms tumor suppressor gene. In neuroblastoma, cytogenetic and molecular studies suggest the existence of a neuroblastoma (suppressor) gene at chromosome 1, at subband 1p36. A constitutional chromosomal deletion syndrome was not known for neuroblastoma. We described a constitutional chromosome translocation t(1;17)(p36.31-21; q11.2-12) in a patient with neuroblastoma. We hypothesised that this translocation, involving the chromosomal band 1p36, predisposed the patient to neuroblastoma development by disturbance of a gene located at the translocation breakpoint. Consequently, identification of the breakpoint flanking markers can be an important step towards the identification and cloning of a neuroblastoma suppressor gene. Radioactive in situ hybridization methods were first applied on the patient's fibroblasts. Soon it became evident that cells with better growth characteristics were needed and that the availability of sufficient patient material was essential. Therefore a somatic cell fusion experiment was performed between the patient's fibroblasts and a thymidine kinase-deficient Chinese hamster cell line. Somatic cell hybrid clones were selected on the presence of the derivative human chromosomes 1 and 17, and of the normal homologues. With the use of fluorescence in situ hybridisation (FISH), the position of chromosome 1 and chromosome 17 markers respective to the breakpoints was determined on chromosome metaphases of the hybrid cell lines containing the human derivative chromosomes. The pronatriodilatine (PND) and the adenovirus 12 modification site (A12M2) were identified as distal and proximal 'single copy' flanking markers of the chromosome 1 breakpoint, respectively. The chromosomal break occurred in a highly repetitive region containing an adenovirus modification site and genes encoding transfer RNA and small U1-RNA genes. The breakpoint on chromosome 17 is located in a region with as proximal boundary the distal part of the neurofibromatosis 1 (NF1) gene locus and as distal flanking marker the SCYA7 locus, encoding the monocyte chemotactic protein-3. Southern blot analysis showed no rearrangements of hybrid DNA using single copy probes for the four flanking markers. Identification of the four breakpoint flanking markers on chromosomes 1 and 17 constitutes a pivotal step for the cloning of the translocation breakpoints and for the identification of a presumed neuroblastoma suppressor gene.
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PMID:[Identification of the breakpoint-flanking markers on chromosomes 1 and 17 of a constitutional translocation T(1;17)(P36;Q12-21) in a patient with neuroblastoma]. 857 70