Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma

Morse, B; Rotherg, Paul G.; South, Victoria J.; Spandorfer, John; Astrin, Susan M.

doi:10.1038/333087a0

Cited by 295 publications

(180 citation statements)

References 15 publications

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“…Retrotransposition of LINE-1 sequences results in a highly unstable branched DNA structure prone to undergoing recombination with accessible elements located nearby or even elsewhere in the genome (Feng et al, 1996). Chromosome deletions and translocations probably caused by retrotransposition events have indeed been observed in several human cancers (Morse et al, 1988;Nagarajan et al, 1990;Miki et al, 1992;Pomykala et al, 1994;Liu et al, 1997). The decrease in promoter methylation in urothelial tumour cells and the occurrence of full-length LINE-1 transcripts in two bladder carcinoma cell lines with hypomethylated DNA (Figure 6) raises the possibility of retrotransposition occurring in urothelial carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Their total number exceeds 10 5 , among which approximately 100 have remained transposition-competent . Disruption of genes by insertion of LINE-1 elements has been found in human cancer and genetic disease (Morse et al, 1988;Miki et al, 1992;Dombroski et al, 1993;Holmes et al, 1994). In addition, DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas LINE-1 sequences have been identified at or near chromosomal translocation sites (Nagarajan et al, 1990;Pomykala et al, 1994;Liu et al, 1997).…”

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confidence: 99%

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DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

et al. 1999

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Summary Since DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome, hypomethylation in human tumours may lead to their reactivation. The methylation status of LINE-1 retroposons was determined in 73 samples of urinary bladder cancers, 34 specimens of renal cell carcinoma and in the corresponding normal tissues by Southern blot analysis. LINE-1 sequences were strongly methylated in normal tissues and were significantly hypomethylated in 69 (95%) urothelial carcinomas, but in none of the renal carcinomas. Hypomethylation in bladder cancers was independent of stage and tended to increase with grade. The methylation status of HERV-K proviral DNA in normal and transformed urothelial cells paralleled that of LINE-1 sequences (r 2 = 0.87). It was shown by ligation-mediated polymerase chain reaction that hypomethylation also extended to the LINE-1 promoter sequence located at the 5′-ends of full-length elements which is repressed by methylation in somatic tissues. Accordingly, full-length LINE-1 transcripts were detected by Northern blot analysis in two urothelial carcinoma cell lines. In contrast, transcripts from HERV-K proviruses were restricted to teratocarcinoma cell lines. Our data indicate that genome-wide DNA hypomethylation is an early change in urothelial carcinoma, but is absent from renal cell carcinoma. The coordinate changes of LINE-1 and HERV-K DNA methylation suggest that hypomethylation in urothelial cancer affects a variety of different retroelements to similar extents. We speculate that decreased methylation of LINE-1 retroelements, in particular, may contribute to genomic instability in specific human tumours such as urothelial carcinoma by rendering these normally repressed sequences competent for transcription and recombination.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

et al. 1999

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“…Pathogenic insertions of both non-autonomous and autonomous elements have been characterized (Kazazian, 1998) like an Alu insertion in human neurofibromatosis (Wallace et al, 1991) or an ETn insertion in murine myotonia (Steinmeyer et al, 1991). Similarly, LINE-1 insertion has been reported to suppress the expression of clotting factor VIII in a case of haemophilia (Kazazian et al, 1988) or of the dystrophin gene in Duchenne's muscular dystrophy (Holmes et al, 1994), to activate c-myc in tumours (Katzir et al, 1985;Morse et al, 1988), and to disrupt the APC gene in colorectal cancer (Miki et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain

et al. 2002

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LINE-1 are endogenous mobile genetic elements that have dispersed and accumulated in the genomes of eukaryotes via germline transposition, with up to 100 000 copies in mammalian genomes. LINE-1 elements transpose by reverse transcription of their own transcript. Transposition requires synthesis of a full-length, sense-strand transcripts and proteins encoded by open reading frame (ORF) 1 and ORF2. Although severely repressed in most normal tissues, LINE-1 occasionally leads to disease by insertional mutagenesis. In the present study, Northern blot and in situ hybridization analyses revealed a template-strand transcription of LINE-1 ORF2 (encoding reverse transcriptase, RT) in lymphoid organs and the liver from MRL-+/+ and Fas-deficient MRL/lpr strains and their normal ancestors. While these sense transcripts are restricted to the nucleus in hepatocytes, they are also found in the cytoplasm in splenocytes. In contrast to transcription, ORF2 translation was detected only in MRL strains, as shown by the cytoplasmic labelling of splenic cells obtained with a monoclonal antibody recognizing the LINE-1 RT. This antibody coprecipitated two proteins of 45 and 12 kDa from MRL/lpr lymphoid organ lysates that were removed by pretreatment with anti-b2-microglobulin antiserum, suggesting a structural association between a LINE-1 product and a major histocompatibility complex class I or class I-like molecule.

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“…LINE-1 repeats constitute about 15% of the human genome, but of the *4610 5 copies of LINE-1 elements in the human genome, only about 30 -60 are estimated to be competent for transposition (Sassaman et al, 1997). There have been occasional reports of cancer-associated retrotransposition-like insertions involving LINE-1 sequences (Miki et al, 1992;Morse et al, 1988), and they may mobilize cellular RNAs at low frequencies (Wei et al, 2001). Their activation can also lead to transcriptional interference involving neighboring genes (Whitelaw and Martin, 2001).…”

Section: Types Of Sequences Affected By Cancer-associated Hypermethylmentioning

confidence: 99%

DNA methylation in cancer: too much, but also too little

2002

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Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

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Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma

Cited by 295 publications

References 15 publications

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain

DNA methylation in cancer: too much, but also too little

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