Distinct modes of transcription read through or terminate at the c-myc attenuator.

Roberts, Sadia; Bentley, David L.

doi:10.1002/j.1460-2075.1992.tb05147.x

Cited by 49 publications

(39 citation statements)

References 48 publications

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“…Nuclear run-on assays Nuclei were prepared from subconfluent cultured cells, and run-on assays and hybridizations were performed as described by Roberts and Bentley (1992). Nylon membranes carrying 5 pg/track of denatured dsDNA were prepared using a dot-blot manifold (Ausubel et al, 1987).…”

Section: Cell Linesmentioning

confidence: 99%

A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines.

1993

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The c-erbB-2 receptor tyrosine kinase proto-oncogene product is overexpressed in 20-30% of breast carcinomas and this has been shown to correlate with poor prognosis. Previous analysis of tumour-derived lines has demonstrated that although the c-erbB-2 gene is often amplified, overexpression can occur from a single-copy gene. Moreover, whether or not the gene is amplified, overexpressing cells produce 6-to 8-fold more mRNA per gene copy than low-expressing cells. In this paper, we examine the possible mechanisms causing this deregulation of c-erbB-2 mRNA accumulation. Nuclear run-on studies indicated that the extra mRNA accumulation was due to increased transcription of the gene in overexpressing cells. Promoter analyses using c-erbB-2 5' flanking sequences linked to CAT showed that the promoter is more active in overexpressing cells. Coupling promoter deletion functional studies with footprinting experiments, using nuclear extracts derived from both low and overexpressing cells, allowed the identification of a DNA-binding protein, OB2-1, which is considerably more abundant in a range of overexpressing lines. We discuss the possible role of OB2-1 in c-erbB-2 overexpression in breast tumour lines.

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Section: Cell Linesmentioning

confidence: 99%

A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines.

1993

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“…We do not know the function of termination at T1, but it is possible that it regulates P1 transcription. Because the T2 site specifically regulates P2 transcription Roberts and Bentley 1992), it was thought previously that P1 RNA was not subject to control by attenuation. The idea that the c-myc gene escapes normal P2 to P1 ) may need to be re-examined in light of the potential P1 attenuation sites identified here.…”

Section: Discussionmentioning

confidence: 99%

“…Transcription from P2 but not P1 is regulated by attenuation at a T-rich sequence called T2 near the 3' end of the first exon Groudine 1986a, 1988;Eick and Bornkamm 1986;Nepveu and Marcu 1986;Wright and Bishop 1989;Roberts and Bentley 1992). A factor called MElal has been implicated in the function of the P2 promoter as well as termination at T2 and at the 3' end of the human complement C2 gene Hall 1990;Miller et al 1989;Ashfield et al 1991).…”

mentioning

confidence: 99%

A protein-binding site in the c-myc promoter functions as a terminator of RNA polymerase II transcription.

Roberts

Purton²,

Bentley³

1992

Genes Dev.

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Termination of transcription not only allows polymerases that have completed RNA synthesis to recycle, but it also has important functions in transcriptional regulation and in preventing promoter interference. The molecular basis for termination by RNA polymerase II (pol II} is unclear, however. We have identified a termination site in the promoter region of the c-myc gene, whose function correlates with DNA binding by a nuclear factor. When the c-myc gene was transcribed in injected Xenopus oocytes or a HeLa nuclear extract, a fraction of RNA initiated at the first promoter, P1, terminated at two positions, T1A and TIB, which flank the TATA box of the second promoter, P2. T1B is a T-rich sequence that resembles previously identified attenuation sites, but TIA appears to represent a different class of termination site. TIA is situated -10 bases upstream of an element that overlaps the P2 TATA box. Mutagenesis of this element affected both the efficiency and the position at which termination occurred. A 28-base sequence including this element caused a low level of termination when inserted into the ~-globin gene in either orientation. This sequence bound a factor called TBF I (terminator-binding factorl, whose binding specificity correlated with T1A terminator function. We suggest that TBF I may function as a pol II termination factor.

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“…Given the similarity of c-myc messenger RNA concentrations when cells are exposed to cyclic AMP or actinomycin D, I was surprised by the results of the transcription run-off studies. Based on previous studies by numerous investigators I expected that the mechanism of cyclic AMP inhibition of c-myc gene expression would be attenuation (29)(30)(31)(32)(33) which usually occurs at the end of the first exon (34) (that is unexpressed) although has been reported to occur between the P1 and P2 promoter (35,36).…”

Section: Methodsmentioning

confidence: 99%

The effect of cyclic-AMP on the regulation of c-myc expression in T lymphoma cells.

Albert

1995

J. Clin. Invest.

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Myc is implicated in the control of growth in a variety of cell types. I investigated c-myc gene expression in several lymphoid cell lines to determine the response to cyclic AMP. Cyclic AMP causes a precipitous decline in c-myc message concentration that precedes G1 cell cycle arrest in wild type S49 cells but not in KIN-cells that lack cAMP dependent PKA activity. In wild-type S49 cells washout of cyclic AMP restores c-myc message levels within 2 h but does not relieve the G1 arrest until 10 h later. Transcription runoff studies demonstrate inhibition of both transcriptional initiation and prolongation of initiated transcripts. However, the degree of inhibition is insufficient to explain the absence of detectable myc message suggesting that the predominant effect of cyclic AMP is to destabilize the c-myc message. In contrast to wild-type cells, the "Deathless" mutant S49 cell line is viable when arrested in G1 by exposure to cyclic AMP and has preserved c-myc expression. Thus, in S49 cells down regulation of c-myc expression appears to be associated with loss of viability rather than G1 cell cycle arrest. Interestingly, CEM human T lymphoma cells do not arrest in G1 phase when exposed to cyclic AMP in spite of losing detectable c-myc gene expression. This suggests that in some T lymphoma cells c-myc gene expression may not be necessary for cell cycle progression and proliferation. (J. Clin. Invest.

show abstract

Distinct modes of transcription read through or terminate at the c-myc attenuator.

Cited by 49 publications

References 48 publications

A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines.

A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines.

A protein-binding site in the c-myc promoter functions as a terminator of RNA polymerase II transcription.

The effect of cyclic-AMP on the regulation of c-myc expression in T lymphoma cells.

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