Transcriptional activation of the translocated c-myc oncogene in mouse plasmacytomas: Similar RNA levels in tumor and proliferating normal cells

Keath, Elizabeth J.; Kelekar, Ameeta; Cole, Michael

doi:10.1016/0092-8674(84)90382-9

Cited by 118 publications

(71 citation statements)

References 28 publications

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“…On a per cell basis, however, the total atnount of c-myc RNA in leukemic blast cells actually has increased more than indicated by the specific measurement of c-myc RNA relative to total mRNA because flow cytometric measurements of RNA with acridine orange staining have shown that the mean RNA content of leukemia cells is approxi- mately twofold higher than that in normal thymocytes (14). Similar results were reported in mouse plasmacytomas in which relative c-myc RNA levels were only four times higher than those in quiescent B cells (7). In this latter work it was estimated that tumor cells contained eight times more RNA resulting in a 30-fold-higher level of c-myc RNA per cell compared with controls.…”

supporting

confidence: 75%

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Reicin¹,

Yang²,

Marcu³

et al. 1986

Mol. Cell. Biol.

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A high frequency (.65%) of thymomas induced by mink cell focus-forming virus 69L1 in AKR/J mice contain proviral integrations which are clustered 0.7-kilobase upstream of the c-myc oncogene predominantly in the opposite transcriptional orientation. Blot hybridization experiments showed that on the average there was only a twofold elevation of steady-state c-myc RNA in the thymomas as compared with levels in normal AKR/J thymocytes. Such an increase would not appear to be sufficient as a mechanism of oncogene activation in this system. In contrast, Si nuclease analysis of transcripts initiated from the two known c-myc promoters indicated a strong shift in promoter usage in virtually all thymomas tested. In normal thymus the ratio of transcripts initiated from the proximal promoter P1 to the distal promoter P2 was 0.2 to 0.3. In contrast, most of the thymomas tested (18 of 23) showed an average P1/P2 ratio of 1.2 regardless of whether or not proviral integrations could be detected within a 21-kilobase EcoRI fragment containing the three c-myc exons. We conclude that alterations in P1/P2 ratios are good indicators of c-myc deregulation in thymic lymphomas.The c-myc oncogene has been implicated in a variety of malignant neoplasms. In lymphoid tumors of both B-and T-cell lineages activation of c-myc has been associated with DNA rearrangements at the c-myc locus caused by either chromosomal translocations or retrovirus insertions (for-a recent review, see reference 25). Recently, we reported murine leukemia virus proviral integrations into the c-myc locus in 65% of thymic lymphomas induced by intrathymic injection of mink cell focus-forming virus (MCF) 69L1 into 40-day-old AKR/J mice (13). In this report we measured steady-state levels of both total c-myc RNA and c-myc transcripts initiated from each of the two known promoters of the gene to study the effect of proviral integration on expression of the c-myc oncogene. We present evidence that expression of c-myc is not increased markedly in MCFinduced thymomas but is deregulated in tumors as evidenced by a reversal of normal promoter usage. Altered levels of the two c-myc transcripts also were observed in many instances in which a proviral integration was not detected near c-myc.A map of MCF proviral integration sites for 40 independent primary thymomas which have been analyzed to date is shown in Fig. 1. Most (32 of 40) of the proviral integrations were in the reverse transcriptional orientation to c-myc and were distributed about a median distance 0.7-kilobase (kb) 5' of exon 1, a finding similar to that reported by other workers (3,9,19). Of the eight tumors with colinear proviral integrations, only two of them, with insertions at +0.7 kb and +5.2 kb, were available for analysis in this study.Steady-state levels of c-myc RNA were measured by slot-blot analysis of total cellular RNA (Fig. 2a). Samples of total RNA (2) in 4.6 M formaldehyde-7.5 x SSC (0.1 M sodium chloride, 0.01 M sodium citrate) were heated at 65°C for 15 min, diluted serially, and applied to two se...

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supporting

confidence: 75%

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Reicin¹,

Yang²,

Marcu³

et al. 1986

Mol. Cell. Biol.

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“…The transcription factor c-Myc is a well known oncogene (23,24), which enhances cell proliferation by regulating cell-cycle regulators, including cyclin D1 and E2F1 (15,16). Our data provide evidence that R1 interacts and colocalizes with c-Myc in SK-N-BE(2)-C cells.…”

Section: R1 and C-myc Enhance Proliferation Via Similar Mechanismssupporting

confidence: 51%

Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

Ou¹,

Chen²,

Shih

2006

Proc. Natl. Acad. Sci. U.S.A.

147

145

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Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2͞CDCA7L͞JPO2) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and R1 in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.c-Myc ͉ caspase-3 ͉ p38 kinase ͉ proliferation ͉ transcription factor M onoamine oxidases (MAOs) A and B, located on the outer mitochondria membrane with a 70% amino acid sequence identity (1, 2), catalyze the oxidative deamination of biogenic and dietary amines including monoamine neurotransmitters serotonin, norepinephrine, dopamine, and phenylethylamine. MAO plays important roles in several psychiatric and neurological disorders (3). MAO exists in two forms, MAO A and MAO B. Their catalytic activity generates H 2 O 2 and nitrogen species, which are toxic products and may cause oxidative damage to mtDNA and have potential implications for apoptosis, aging, and neurodegenerative processes (4).The in vivo function of MAO A and MAO B has been studied extensively in MAO A and MAO B knockout (KO) mice (5-7). The regulation of MAO A and MAO B gene expression by extracellular stimulation, phorbol 12-myristate 13-acetate (PMA), has also been examined. PMA selectively increases MAO B but not MAO A gene expression by activation of protein kinase C and mitogen-activated protein kinase (MAPK) signaling pathways (8).Ample evidence has indicated an important role for MAO A in apoptosis. MAO A expression has been shown to increase after the depletion of neurotrophic factor mediated by p38 kinase in PC12 cells (9). A MAO A inhibitor, clorgyline, was able to protect cells from apoptosis induced by serum starvation in human melanoma m14 cells (10). More recently, MAO A has been found to be a target of a dopaminergic neurotoxin, N-methyl-(R)-salsolinol, which leads to apoptosis in a human neuroblastoma SH-SY5Y cell line (11). This apoptotic activity co...

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“…All of these plasmacytomas, except J606, have c-myc genes translocated to the Ca locus, although some of these tumors express isotypes other than alpha. M104E (immunoglobulin M) is unusual in that it has a c-myc gene translocated just 3' of the Ca gene (24). In all cases, the translocated c-myc gene was significantly more sensitive to DNase I than the normal c-myc gene.…”

mentioning

confidence: 99%

“…This demonstrates a requirement for B-cell-specific factors and suggests that B-cell factors normally involved in immunoglobulin gene transcription may also activate the cryptic c-myc promoters translocated adjacent to immunoglobulin genes. With few exceptions (7,11,16,22,39), the known immunoglobulin heavy-chain enhancer (3,19,29,30) does not remain on the same chromosome as the translocated c-myc gene and thus is not responsible for this activation (18,24,29,35). Since DNase I-sensitive structure is associated with active genes (23,44 46), we reasoned that an analysis of c-myc gene chromatin in plasmacytomas might provide insight into mechanisms responsible for activation of the cryptic promoters.…”

mentioning

confidence: 99%

“…Frequently, translocation in plasmacytomas removes the normal c-myc promoters, and the translocated c-myc gene is transcribed from cryptic promoters located in the intervening sequence 5' of the first coding exon (4,5,24,34,40). Although steady-state levels of transcripts from such translocated genes vary, they are usually relatively high, whereas transcripts from the normal c-myc gene on the untranslocated chromosome are undetectable (1,2,4,34,40).…”

mentioning

confidence: 99%

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An active chromatin structure acquired by translocated c-myc genes.

Kakkis¹,

Prehn²,

Calame³

1986

Mol. Cell. Biol.

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We used general sensitivity to DNase I digestion to analyze the chromatin structure of c-myc genes in seven murine plasmacytomas. In every case, the 3' portion of c-myc juxtaposed with Ca displayed a much more DNase I-sensitive chromatin structure than untranslocated c-myc or, in one case analyzed, the reciprocally translocated 5' portion. Our data suggest the presence of regulatory sequences near the Ca gene segment.

show abstract

Transcriptional activation of the translocated c-myc oncogene in mouse plasmacytomas: Similar RNA levels in tumor and proliferating normal cells

Cited by 118 publications

References 28 publications

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

An active chromatin structure acquired by translocated c-myc genes.

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