Loss of heterozygosity on chromosome 11 in sporadic gastrinomas

Sawicki, Mark; Wan, Yu‐Jui Yvonne; Johnson, Carey L.; Berenson, James R.; Gatti, Richard A.; Passaro, Edward

doi:10.1007/bf00194320

Cited by 46 publications

(20 citation statements)

References 17 publications

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“…breast cancer and parathyroid tumours), resulting in transcriptional up-regulation. However, previous studies did not reveal gross cytogenetic rearrangement or DNA amplification in the region of cyclin D1 in sporadic PETs (Sawicki et al 1992, Terris et al 1998, Speel et al 1999. Cyclin D1 expression in sporadic PETs is therefore likely to occur through a transcriptional or a post-transcriptional mechanism.…”

Section: Cyclin D1 Overexpression Occurs At the Post-transcriptional mentioning

confidence: 91%

Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours

Ss¹,

Wu²,

Shimoide³

et al. 2003

Journal of Endocrinology

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Pancreatic endocrine tumours (PETs) occur sporadically or are inherited as part of the multiple endocrine neoplasia type-1 syndrome. Little is known about the molecular events leading to these tumours. Cyclin D1, a key regulator of the G1/S transition of the cell cycle, is overexpressed in a variety of human cancers as well as certain endocrine tumours. We hypothesized that similar to other endocrine tumours, cyclin D1 is overexpressed in human sporadic PETs. Cyclin D1 protein overexpression was found in 20 of 31 PETs (65%) when compared with normal pancreatic tissue. Furthermore, Northern blot analysis suggests that cyclin D1 up-regulation occurs at the post-transcriptional level in some PETs. Because the key cell growth signalling pathways p42/p44/ERK (extracellular signal-regulated kinase), p38/MAPK (mitogenactivated protein kinase), and Akt/PKB (protein kinase B) can regulate cyclin D1 protein expression in other cell types, pancreatic endocrine tumours were analysed with phospho-specific antibodies against the active forms of these proteins to elucidate a tissue-specific regulatory mechanism of cyclin D1 in PETs. We found frequent activation of the p38/MAPK and Akt pathways, but down-regulation of the ERK pathway, in cyclin D1 overexpressing PETs. This study demonstrates that cyclin D1 overexpression is associated with human sporadic PET tumorigenesis, and suggests that this up-regulation may occur at the post-transcriptional level. These findings will direct future studies of PETs towards cell cycle dysregulation and the identification of key growth factor pathways involved in the formation of these tumours.

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Section: Cyclin D1 Overexpression Occurs At the Post-transcriptional mentioning

confidence: 91%

Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours

Ss¹,

Wu²,

Shimoide³

et al. 2003

Journal of Endocrinology

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“…Complementing these linkage studies, tumor deletion mapping has been used to narrow the region furMultiple endocrine neoplasia, type 1 (MEN1, MIM ther (Eubanks et al, 1993;Sawicki et al, 1992;Yoshi-131100), is an autosomal dominant inherited disease moto et al, 1989;Larsson et al, 1988;Bystrom et al, that predisposes affected individuals to develop para-1990;Friedman et al, 1989;Radford et al, 1990;Thakthyroid hyperplasia, pancreatic endocrine tumors, and ker et al, 1989;Bale et al, 1991). Both sporadic and pituitary adenomas.…”

Section: Introductionmentioning

confidence: 99%

A Transcript Map Encompassing the Multiple Endocrine Neoplasia Type-1 (MEN1) Locus on Chromosome 11q13

et al. 1997

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“…The gene had been postulated to be a tumour suppressor, as loss of the wild-type allele was found in tumours from MEN1 patients (Larsson et al, 1988). Additional support for its role as a tumour suppressor gene came from the demonstration of loss of heterozygosity in sporadic tumours (Friedman et al, 1989;Thakker et al, 1989;Sawicki et al, 1992;Debelenko et al, 1997b) and is now con®rmed by the identi®cation of somatic MEN1 mutations Zhuang et al, 1997a, b;Toilat et al, 1997;Debelenko et al, 1997a;Farnebo et al, 1998). Inactivating mutations have been reported in half of the parathyroid, pituitary and pancreatic tumours which exhibit a concomitant loss of one MEN1 allele.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the mouse Men1 gene and its expression during development

et al. 1998

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The gene responsible for multiple endocrine neoplasia type 1 (MEN1), a heritable predisposition to endocrine tumours in man, has recently been identi®ed. Here we have characterized the murine homologue with regard to cDNA sequence, genomic structure, expression pattern and chromosomal localisation. The murine Men1 gene spans approximately 6.7 kb of genomic DNA and is comprised of 10 exons with similar genomic structure to the human locus. It was mapped to the pericentromeric region of mouse chromosome 19, which is conserved with the human 11q13 band where MEN1 is located. The predicted protein is 611 amino acids in length and overall is 97% homologous to the human orthologue. The 45 reported MEN1 mutations which alter or delete a single amino acid in human all occur at conserved residues, thereby supporting their functional signi®cance. Two transcripts of approximately 3.2 and 2.8 kb were detected in both embryonal and adult murine tissues, resulting from alternative splicing of intron 1. By RNA in situ hybridization and Northern analysis the spatiotemporal expression pattern of Men1 was determined during mouse development. Men1 gene activity was detected already at gestational day 7. At embryonic day 14 expression was generally high throughout the embryo, while at day 17 the thymus, skeletal muscle, and CNS showed the strongest signal. In selected tissues from postnatal mouse Men1 was detected in all tissues analysed and was expressed at high levels in cerebral cortex, hippocampus, testis, and thymus. In brain the menin protein was detected mainly in nerve cell nuclei, whereas in testis it appeared perinuclear in spermatogonia. These results show that Men1 expression is not con®ned to organs a ected in MEN1, suggesting that Men1 has a signi®cant function in many di erent cell types including the CNS and testis.

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Loss of heterozygosity on chromosome 11 in sporadic gastrinomas

Cited by 46 publications

References 17 publications

Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours

Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours

A Transcript Map Encompassing the Multiple Endocrine Neoplasia Type-1 (MEN1) Locus on Chromosome 11q13

Characterization of the mouse Men1 gene and its expression during development

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