RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon.

Soares, Marcelo B.; Schon, Eric A.; Henderson, A; Karathanasis, S K; Cate, R; Zeitlin, Scott; Chirgwin, John M.; Efstratiadis, Argiris

doi:10.1128/mcb.5.8.2090

Cited by 229 publications

(149 citation statements)

References 37 publications

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“…The insulin I gene duplication is believed to have resulted from the integration of a cDNA produced by viral reverse transcription of an aberrant insulin II mRNA in a murine ancestor (30). We speculate that inefficient splicing of intron 1, such as we have observed, could explain why intron 1 was retained in the template mRNA.…”

Section: Discussionmentioning

confidence: 64%

“…The length of intron 2 varies widely among species, but intron 1 is generally small (118 bp in mouse insulin II to 179 bp in human). Most species have a single insulin gene; but in rats and mice, a duplication has resulted in a second copy of the insulin gene that lacks the second intron (11)(12)(13). The ancestral and duplicate genes are termed insulin II and insulin I, respectively.…”

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confidence: 99%

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Regulation of insulin preRNA splicing by glucose

Wang

Shen

Najafi

et al. 1997

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

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Glucose tightly regulates the synthesis and secretion of insulin by ␤ cells in the pancreatic islets of Langerhans. To investigate whether glucose regulates insulin synthesis at the level of insulin RNA splicing, we developed a method to detect and quantify a small amount of RNA by using the branched DNA (bDNA) signal-amplification technique. This assay is both sensitive and highly specific: mouse insulin II mRNA can be detected from a single ␤ cell (␤TC3 cells or mouse islets), whereas 1 million non-insulinproducing ␣ cells (␣TC1.6 cells) give no signal. By using intron and exon sequences, oligonucleotide probes were designed to distinguish the various unspliced and partially spliced insulin preRNAs from mature insulin mRNA. Insulin RNA splicing rates were estimated from the rate of disappearance of insulin preRNA signal from ␤ cells treated with actinomycin D to block transcription. We found that the two introns in mouse insulin II are not spliced with the same efficiency. Intron 2 is spliced out more efficiently than intron 1. As a result, some mRNA retaining intron 1 enters the cytoplasm, making up Ϸ2-10% of insulin mRNA in the cell. This partially spliced cytoplasmic mRNA is quite stable, with a half-life similar to the completely spliced form. When islets grown in high glucose are shifted to low glucose medium, the level of insulin preRNA and the rate of splicing fall significantly. We conclude that glucose stimulates insulin gene transcription and insulin preRNA splicing. Previous estimates of insulin transcription rates based on insulin preRNA levels that did not consider the rate of splicing may have underestimated the effect of glucose on insulin gene transcription.Insulin, the key signal for energy storage, is synthesized and secreted by the ␤ cells of the pancreatic islets of Langerhans in mammals. Insulin synthesis and secretion is tightly regulated by glucose, which serves as a signal of the energy state of the organism. Synthesis of mature insulin is a multistep process and glucose regulates synthesis at several of these steps, including transcription (1), mRNA stabilization (2), translation (3, 4), and processing proinsulin to insulin (5).The level of insulin mRNA available in the cytoplasm for translation to preproinsulin depends on the relative rates of insulin mRNA production and degradation. Glucose regulates both insulin gene transcription and insulin mRNA degradation (1, 2). Transcription rate alone, however, does not determine the production rate of cytoplasmic insulin mRNA. Prior to export from the nucleus, preRNAs are spliced and a 5Ј m 7 GpppN cap and 3Ј adenosines are added. These processes are not independent: splicing accelerates polyadenylylation, and both are important for nuclear export (6-8).Insulin preRNA in most species contains two introns. The sequences of the introns show little evidence of evolutionary conservation, but the positions of the introns are highly conserved (9, 10). The length of intron 2 varies widely among species, but intron 1 is generally small (118 ...

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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

Regulation of insulin preRNA splicing by glucose

Wang

Shen

Najafi

et al. 1997

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

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“…Analysing structural features of the gene encoding insulin, Soares et al reported that Ins1 was generated by an RNA-mediated duplication-transposition event involving a transcript of Ins2 [1]. In addition, only Ins2 is expressed in the NOD thymus with both genes expressed in islet beta cells [3,16,17].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Ins1 lacks an intron present in Ins2. These structural features suggest that Ins1 was generated by an RNA-mediated duplication-transposition event involving a transcript of Ins2, which was reinserted into the genome (retroposon) [1].…”

Section: Introductionmentioning

confidence: 99%

A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2

Babaya¹,

Nakayama²,

Moriyama

et al. 2006

Diabetologia

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“…Unlike most species, rats possess two non-allelic insulin genes which are highly homologous within the protein coding sequences; this homology extends approx. 500 bp upstream from the cap site of the messenger RNA [7]. The rat insulin I gene, which has lost one of the two intervening sequences present in the rat insulin II gene, is believed to have arisen via an RNAmediated transposition event from a transcript which was initiated upstream from the normal initiation site of the rat insulin II gene [7].…”

Section: Introductionmentioning

confidence: 99%

Tissue‐specific binding of a nuclear factor to the insulin gene promoter

Sample

Steiner

1987

FEBS Letters

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Using a DNA-binding gel mobility shift assay, a protein-DNA complex was detected using the rat II insulin promoter and a nuclear extract from rat insulinoma cells. This complex was detected using extracts from other insulin-producing cell lines but was not found using nuclear extracts from non-insulin-producing pancreatic cell lines or other cell types. Binding of the tissue-specific protein to the labelled promoter fragment was effectively competed by both rat and human insulin genes but not by the SV40 TATA box. This protein-DNA interaction may be involved in tissue-specific regulation of insulin gene expression.

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RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon.

Cited by 229 publications

References 37 publications

Regulation of insulin preRNA splicing by glucose

Regulation of insulin preRNA splicing by glucose

A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2

Tissue‐specific binding of a nuclear factor to the insulin gene promoter

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