Sequence of the human insulin gene

Bell, Graeme I.; Pictet, Raymond; Rutter, William J.; Cordell, Barbara; Tischer, Edmund; Goodman, Howard M.

doi:10.1038/284026a0

Cited by 500 publications

(205 citation statements)

References 36 publications

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“…In contrast to other B cell lines [5], HIT cells retain the essential insulin secretory characteristics of the normal differentiated B cell, including responsiveness to Correspondence address: P. Hammonds, Nuffield Dept of Clinical Biochemistry, John Radcliffe Hospital, Headington, Oxford OX3 9DU, England glucose [4,6]. In the Syrian hamster, as in humans [7], there is a single preproinsulin gene, whereas rats and mice possess two non-allelic genes [8]. Moreover, there is evidence that the two rat preproinsulin genes may be differentially regulated under stimulatory conditions [9].…”

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confidence: 99%

Glucose regulates preproinsulin messenger RNA levels in a clonal cell line of simian virus 40‐transformed B cells

Hammonds

Schofield²,

Ashcroft

1987

FEBS Letters

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In HIT-T15 cells grown in the absence of glucose, Northern blot analysis of total RNA revealed a major 0.5 kb preproinsulin (pp1) mRNA transcript which co-migrated with the mature transcript from a human insulinoma. In 4 h tissue cultures, glucose (2-20 mM) stimulated HIT cell pp1 mRNA levels in a markedly dose-dependent manner. Glucose-stimulated pp1 mRNA was (i) inhibited by actinomycin D, suggesting that regulation may be in part transcriptional, and (ii) potentiated by agents known to activate B cell protein kinases. HIT cells represent a unique model for investigating long term regulation of insulin gene expression and biosynthesis.

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mentioning

confidence: 99%

Glucose regulates preproinsulin messenger RNA levels in a clonal cell line of simian virus 40‐transformed B cells

Hammonds

Schofield²,

Ashcroft

1987

FEBS Letters

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“…The other signal, an arginine residue between Np and the glycoprotein, is preserved in exon C. Genes encoding other polyproteins (Herbert, 1981;Numa and Nakanishi, 1981) like the pro-enkephalins (Herbert, 1981;Kakidani et al, 1982;Noda et al, 1982;Gubler et al, 1982;Legon et al, 1982) apparently adopted a mechanism where repetitive enkephalin units together with spacer regions and proteolytic cleavage signals are encoded within a single exon. In these cases pre-existing introns separating the functional units might have been lost during evolution (Perler et al, 1980;Bell et al, 1980) after repetition of an ancestral gene Gubler et al, 1982;Legon et al, 1982). Except for an ancient gene duplication within the neurophysin exon (B), this mechanism does not appear to have played a significant role in the evolution of the AVP-Np gene, which better fits an exon shuffling model (Gilbert, 1978;Crick, 1979).…”

Section: Discussionmentioning

confidence: 99%

Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor

1983

The EMBO Journal

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The rat arginine vasopressin-neurophysin precursor gene has been isolated from a genomic library cloned in X phage Charon 4A. Restriction mapping and nucleotide sequence analysis demonstrated that the gene is 1.85 kilobase pairs long and contains two intervening sequences located in the protein coding region. Exon A encodes a putative signal peptide, the hormone arginine vasopressin and the variable N terminus of the carrier protein neurophysin, exon B encodes the highly conserved middle part of neurophysin and exon C its variable C terminus together with glycoprotein. Thus, the three functional domains of the precursor -argiline vasopressin, neurophysin, glycoprotein -are encoded on three distinct exons.

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“…Two new DNA constructs were used for the generation of the triple transgenic mice. The first construct contained a 1,165-bp fragment of a rat insulin gene 1 promoter (14), a mouse L-selectin cDNA (9), and the untranslated 3Ј end of the human insulin gene (15). The 1,165-bp fragment from the rat insulin gene 1 consists of a 986-bp 5Ј-flanking region, the first exon, the first intron, and 7 bp of the second exon, which all are untranslated.…”

Section: Methodsmentioning

confidence: 99%

L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis

Qian

Hanahan

Weissman

2001

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

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L-selectin mediates homing of lymphocytes to lymph nodes (LN).Transgenic mice that express rat insulin promoter regulated simian virus 40 Tag (RIP-Tag) develop large, local cancers that metastasize to liver but not LN. To test whether this lack of LN metastases reflects their absence from the circulation, transgenic mice were produced that express Tag (T), L-selectin (L), and Escherichia coli LacZ (Z), in pancreatic ␤ cells. LTZ mice developed insulinomas that specifically had LN metastases; metastasis was blocked by an anti L-selectin mAb. LacZ ؉ tumor cells from these LN homed to secondary LN upon transfer. These results suggest that the highly vascularized islet carcinomas are shedding tumor cells into the bloodstream, which is a necessary but insufficient condition for metastasis to occur; L-selectin can facilitate homing of such tumor cells to LN, resulting in metastasis.M etastatic disease is a significant parameter of tumor progression and the primary determinant of poor prognosis. Bloodborne metastasis is a major pathway by which tumor cells seed additional sites in the body. The bloodborne metastatic process can, in principle, be divided into four steps: (i) invasion of cancer cells that have detached from the primary tumor into the vascular system; (ii) dissemination of tumor cells via the circulatory system; (iii) extravasation of tumor cells at a distinct site; and (iv) establishment of a new tumor at that location. Metastasis has principally been studied by using two types of assays (1, 2): i.v. injection of tumor cells to assess their ability to survive, adhere to blood vessel endothelium, extravasate, and establish tumors; and injection into local tissue (usually s.c.) to assess their capability to metastasize from a primary tumor mass. Neither of these assays accurately mimics the metastatic process of endogenously arising primary tumors. The establishment of metastatic lesions requires not only tumor cell proliferation but also induction of angiogenesis to sustain tumor growth (3). In general, however, it remains unclear which events are rate limiting for metastasis to occur. Are tumor cells frequently shed from tumors undergoing persistent neovascularization? Or is it dissemination via the bloodstream or the ability to extravasate that is limiting? We have sought to address these questions in a transgenic mouse model of endogenous primary multistage carcinogenesis in which metastasis is infrequent. We have done this by producing transgenic mice that express L-selectin on endogenous primary insulinomas and then asking whether the frequency of metastasis is affected.RIP-Tag transgenic mice develop islet cell carcinomas as a result of the simian virus 40 Tag oncogene expression in islet ␤ cells (4). Tumor development proceeds through a series of well defined stages, which include: a dysplasia͞carcinoma in situ-like stage, an angiogenic islet stage (5, 6), the solid tumor stage, in which tumors vary in regard to their size and apoptotic incidence (7), and an invasive carcinoma stage (6-8). Metastas...

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Sequence of the human insulin gene

Cited by 500 publications

References 36 publications

Glucose regulates preproinsulin messenger RNA levels in a clonal cell line of simian virus 40‐transformed B cells

Glucose regulates preproinsulin messenger RNA levels in a clonal cell line of simian virus 40‐transformed B cells

Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor

L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis

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