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Query: UNIPROT:P06889 (Mol)
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A new promoter of the human c-myc gene called P0, with multiple RNA start sites, was mapped over 500 bases upstream of the two previously identified promoters, P1 and P2. Sequencing full-length cDNA clones of P0 RNAs revealed two open reading frames upstream of that for the P64c-myc protein. P0 RNA is located on polyribosomes and released by puromycin, indicating that it functions as an mRNA. In vitro translation of RNA synthesized from the cloned cDNAs predicts that P0 transcripts are translated into a novel 12.5-kilodalton protein corresponding to the first open reading frame. The regulation of P0 RNA was studied in the B-cell lymphoma cell line Manca, in which only the translocated c-myc allele lacking exon 1 was thought to be active. However, we found that P0 transcription and the DNase I-hypersensitive site associated with this promoter persist on the untranslocated allele, even though P1/P2 transcription as measured by a nuclear runoff assay was repressed. These results suggest that allelic exclusion of c-myc expression in this B-cell lymphoma is caused by a repression of transcription which is specific to the P1/P2 promoters. We previously reported a block to elongation of transcription near the 3' end of exon 1 in the wild-type c-myc gene, which results in an excess of exon 1 over exon 2 transcription (5a). In contrast, we found that in the Daudi B-cell lymphoma, which retains exon 1 in the active allele, equimolar transcription of exons 1 and 2 occurs. This result suggests a model for the activation of c-myc in B-cell lymphomas.
Mol Cell Biol 1986 Oct
PMID:Novel promoter upstream of the human c-myc gene and regulation of c-myc expression in B-cell lymphomas. 354 May 91

We have cloned and sequenced the translocated c-myc gene from the Burkitt's lymphoma CA46 cell line that carries a reciprocal translocation between chromosomes 8 and 14. The breakpoint lies within the first intron of c-myc, so that the first noncoding exon of the gene remains on the 8q- chromosome. The second and third coding exons are translocated to the 14q+ chromosome into the switch region of C-alpha 1. The orientation of the c-myc gene with relationship to alpha 1 is 5' to 5', with directions of transcription in opposite orientation. DNA sequencing studies predict five changes in the amino acid sequence of the myc protein, two of which occur in a region within the second exon which is highly conserved in evolution. Southern blotting data indicate that the first exon of c-myc is rearranged 3' to 3' with the pseudo-epsilon gene. Because CA46 cells contain two rearranged mu genes, the translocation must have occurred after immunoglobulin rearrangement. The position of the breakpoint in CA46 occurs within a 20-base-pair region of the first intron of c-myc to which breakpoints have been mapped for two additional B-cell lymphomas with the t(8;14) translocation, ST486 and the Manca cell line. The region of the heavy chain locus to which c-myc has translocated is different in each case. Comparisons have been made of the levels of transcripts of the translocated c-myc gene in ST486 and CA46, where the gene is not associated with the heavy chain enhancer, with its expression in the Manca cell, in which it is. The c-myc gene is transcribed at similar levels in all three cases.
Mol Cell Biol 1985 Mar
PMID:Cloning and sequencing of a c-myc oncogene in a Burkitt's lymphoma cell line that is translocated to a germ line alpha switch region. 392 23

A murine monoclonal antibody, HNK-1, is known to react with some human leukocytes including all natural killer (NK) cells in peripheral blood. The distribution of cells reacting with this antibody (HNK-1+ cell) was studied in human peripheral lymphoid organs, consisting of five lymph nodes, two specimens of gastric mucosa with lymphoid tissue, two tonsils, one appendix, and two thymuses. Fourteen cases of malignant lymphoma (ML) were also examined. For the demonstration of HNK-1+ cells, the peroxidase-antiperoxidase (PAP) bridge method was applied to cryostat sections of these specimens. It was found that in normal lymphoid organs most HNK-1+ cells were located in lymph follicles, especially in germinal centers, and some were found in 'mixed' regions which indicate outsides of both the follicles and T-zones. Amongst the ML, large clusters of HNK-1+ cells were observed only in two cases of follicular lymphoma, although a few scattered HNK-1+ cells were noted in other ML, including five diffuse B-cell lymphomas, six T-cell lymphomas and one null cell lymphoma. The possible significance of these findings is discussed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:The distribution of cells expressing a natural killer cell marker (HNK-1) in normal human lymphoid organs and malignant lymphomas. 613 99

An analysis of the sizes and sequence content of nuclear RNA transcripts of the heavy-chain locus in two B-cell lymphomas, 70Z/3 and 38C-13, and in selected hybridoma derivatives of 38C has led to the identification of two distinct precursors of the mRNAs encoding the membrane and secretory forms of mu chain. These precursors, termed Pm1 and Ps1, extend from a common 5' terminus (presumably the cap site) to alternative polyadenylation sites located 3' of the membrane and secretory tailpieces, Pm1 and Ps1 are present in similar amounts in lymphomas, indicating roughly equivalent usage of the two polyadenylation sites, whereas Ps1 much greater than Pm1 in hybridomas, indicating that mature plasma cells produce a trans-acting factor which enhances cleavage at the proximal (muS) site. The lymphomas also synthesize several nonproductive or sterile mu (Smu) transcripts from the second H allele. One class of sterile mu transcripts appears to be initiated about 1 kilobase downstream from the JH4 element. In 70Z, in which the nonproductive H allele has undergone a D1J2 fusion, another initiation site was located about 0.3 kilobase upstream of the D1 element. The sterile mu transcripts exhibit the same regulated termination at alternative polyadenylation sites as the mu mRNA precursors, although their rate of production is not necessarily coupled to that of the productive allele. This analysis has also defined probable processing pathways for productive and sterile components in which there is a 5' leads to 3' order for the excision of the large introns.
Mol Cell Biol 1983 Jul
PMID:Characterization of productive and sterile transcripts from the immunoglobulin heavy-chain locus: processing of micron and muS mRNA. 641 70

The SP6 kappa-promoter pentadecamer (pd) element was found to be unable to stimulate transcription when present in one copy as the only promoter element in a minimal promoter but showed weak stimulatory activity when present as a multimer (four copies). One copy of the pd element acted synergistically with an octamer element, but not with a SP1 site, to stimulate transcription. The effect was orientation dependent with regard to the pd element. Gel shift analysis showed that pd-binding proteins were expressed in transformed as well as nontransformed B lymphocytes, irregardless of their differentiation stage, and in HeLa cells. Two major complexes, binding to different sites within the pd element, were observed in gel shifts. A low-molecular-weight form dominated in resting cells, while a higher-molecular-weight form appeared after mitogenic stimulation. Southwestern analysis showed that the low-molecular-weight pd-binding protein had a molecular mass of 35 kDa, which was confirmed by fractionation by denaturating polyacrylamide gel electrophoresis and molecular sieving. The higher-molecular-weight complex was sensitive to detergent treatment, while the low-molecular-weight complex was not. Mutation analysis showed that the two pd-binding complexes interacted with distinct sites within the element and that dual occupancy was required for functional activity. The functional synergy between the pd element and the octamer was more pronounced in plasmacytomas than in B-cell lymphomas.
Mol Cell Biol 1995 Mar
PMID:Pentadecamer-binding proteins: definition of two independent protein-binding sites needed for functional activity. 786 27

In an effort to identify aberrantly expressed genes in v-rel-induced tumors, monoclonal antibodies were developed that reacted selectively with avian B-cell tumors. One antibody, HY78, immunoprecipitated a 120-kDa glycoprotein (p120) from cells that express v-rel. N-terminal amino acid sequencing of p120 identified a 27-amino-acid sequence that is also present in DM-GRASP, an adhesion molecule belonging to the immunoglobulin superfamily. Evidence from tissue distribution, immunological cross-reaction, PCR amplification, cDNA cloning, and DNA sequence shows that p120 is indeed DM-GRASP. Northern (RNA) analysis using a probe from the DM-GRASP gene identified a 5.3-kb transcript in mRNA from bursa, thymus, and brain as well as from v-rel-induced B-cell lymphomas but not from bursal B cells. The induction of this protein by v-rel during the development of bursal B-cell lymphomas appears, therefore, to be ectopic in nature. Overexpression of v-rel or c-rel in chicken embryonic fibroblasts, B-cell lines, and spleen mononuclear cells induces the expression of DM-GRASP. The ratio of DM-GRASP to v-Rel was fivefold higher than that of DM-GRASP/c-Rel in a B-cell line, DT95. Interestingly, the presence of HY78 antibody inhibits the in vitro proliferation of v-rel-transformed cells but not cells that immortalized by myc. These data suggest that DM-GRASP is one of the genes induced during v-rel-mediated tumor development and that DM-GRASP may be involved in the growth of v-rel tumor cells.
Mol Cell Biol 1995 Mar
PMID:v-rel Induces ectopic expression of an adhesion molecule, DM-GRASP, during B-lymphoma development. 786 70

Expression of mRNA for protein kinase C (PKC)-alpha, -beta, -gamma, -delta, -epsilon, -zeta, and -eta has been shown, by polymerase chain reaction-generated isozyme-specific probes, to be cell-type -and differentiation-stage-specific in mouse hemopoietic cells. Recently, we cloned a 2.2-kb mouse PKC -zeta cDNA. In this study, we used the nearly full-length cDNA PKC-zeta probe to demonstrate that expression of PKC-zeta was significantly elevated in lymphocytic neoplasms at both the mRNA and protein levels. Normal brain, kidney, and liver contain 2.4- and 4.4-kb mRNAs, whereas normal lymphoid organs (spleen, thymus, and lymph nodes) express barely detectable amounts of PKC-zeta. These vanishingly small levels of PKC-zeta mRNA did not increase when polyclonal spleen B-cell proliferation and differentiation were induced in vivo with anti-immunoglobulin D antiserum or in vitro with lipopolysaccharide. In contrast, 2.4-kb transcripts of PKC-zeta are abundant in virtually all neoplastic B-lymphocytic cell lines. Furthermore, additional transcripts of a novel size, about 7 and 8 kb, were found in several mature B-cell lymphomas and plasma cell tumors. Western blot analysis of protein extracts from normal B cells and hemopoietic tumors confirmed that these quantitative differences in PKC-zeta mRNA also exist at the protein level. That is, only trace amounts of PKC-zeta protein were detectable in pro-B cells and pre-B cells, but abundant amounts of this isoform were found in protein extracts from most B-cell lymphomas and plasma cell tumors. These findings suggest that this atypical member of the PKC multigene family participate in the multistep process of malignant transformation of lymphocytes.
Mol Carcinog 1994 Nov
PMID:Association of elevated levels of protein kinase C-zeta mRNA and protein with murine B-lymphocytic neoplasia. 794 1

Determination of clonality in B-cell lymphomas is a useful diagnostic adjunct. In situ hybridization (ISH) for the detection of kappa and lambda mRNAs has the potential to overcome some common specimen-related limitations in clonal assessment. Tritium-labeled antisense cRNA probes directed at conserved segments of the constant regions of the kappa and lambda mRNAs were used in an autoradiographic method to detect B-cell clonality. Using these probes, we analyzed 103 formalin-fixed, paraffin-embedded biopsy samples, and the results were subsequently compared to available immunophenotypic (all cases) and genotypic (50 cases) data. Of 103 samples, 82 (80%) had adequate RNA preservation as determined by actin RNA signals, and 73 (89%) of the 82 cases demonstrated concordant clonality assignment by both ISH and immunophenotyping. The remaining nine cases showed a specific form of discordance in that each exhibited no protein (Ig) expression but had evidence of mRNA immunoglobulin light-chain expression. Forty-five (90%) of 50 cases evaluated for immunoglobulin and T-cell receptor beta-gene rearrangements demonstrated concordant results with respect to clonality assignment by ISH. Thus, ISH demonstrates adequate sensitivity with respect to traditional methods of clonality assessment. However, its practical utility awaits the development of nonradioactive detection methods with adequate sensitivity to improve turnaround time.
Diagn Mol Pathol 1994 Sep
PMID:In situ hybridization analysis of lymphoproliferative disorders. Assessment of clonality by immunoglobulin light-chain messenger RNA expression. 798 92

The p53 tumor suppressor protein, which is commonly mutated in human cancers, has been shown to interact directly with virally encoded from papillomavirus, adenovirus, and simian virus 40. The disruption of p53 function may be required for efficient replication of certain viruses and may also play a role in the development of virally induced malignancies. Infection with Epstein-Barr virus (EBV) has been associated with the development of B-cell lymphomas and nasopharyngeal carcinoma. Here we show that the EBV immediate-early protein, BZLF1 (Z), which is responsible for initiating the switch from latent to lytic infection, can interact directly in vitro and in vivo with the tumor suppressor protein, p53. This interaction requires the coiled-coil dimerization domain of the Z protein and the carboxy-terminal portion of p53. Overexpression of wild-type p53 inhibits the ability of Z to disrupt viral latency. Likewise, Z inhibits p53-dependent transactivation in lymphoid cells. The direct interaction between Z and p53 may play a role in regulating the switch from latent to lytic viral infection.
Mol Cell Biol 1994 Mar
PMID:Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency. 811 24

Following our recent reports of detecting clonal immunoglobulin and T-cell receptor gene rearrangements by the polymerase chain reaction, we have improved and simplified the technique for use in diagnostic histopathology laboratories and determined, on coded samples, the sensitivity, specificity, and reproducibility of the modified methodology in distinguishing malignant lymphoma from reactive lymphoid hyperplasia and nonlymphoid tumors. Using only three primer pairs for the immunoglobulin heavy chain and T-cell receptor beta and gamma chain genes on well-characterized lesions of widely varying morphology and immunophenotype, clonal rearrangements were detected in 65% of B-cell lymphomas, and 77-82% of T-cell tumors. Specificity and observer consistency ranged from 93-97%. The method requires very careful control, particularly to avoid misinterpretation of results because of contamination and nonspecific amplification, but in its present form is relatively simple and inexpensive, and gives results on single paraffin-embedded sections within 24 h.
Diagn Mol Pathol 1993 Dec
PMID:Evaluation of sensitivity, specificity, and reproducibility of an optimized method for detecting clonal rearrangements of immunoglobulin and T-cell receptor genes in formalin-fixed, paraffin-embedded sections. 811 99


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