A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas

Westermark, Per; Wernstedt, Christer; Wilander, Erik; Sletten, Knut

doi:10.1016/0006-291x(86)90708-4

Cited by 469 publications

(212 citation statements)

References 20 publications

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“…IAPP was first isolated from amyloid deposits in an insulin-producing pancreatic tumor and from pancreatic islet amyloid in patients with type 2 diabetes mellitus (31,32). Highest levels of this protein are normally encountered in pancreatic beta cells.…”

Section: Genechip Analysis Of Genes Regulated By Rnai Knockdown Of Mamentioning

confidence: 99%

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Wang²,

Stormo³

et al. 2004

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

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We have previously characterized a transgenic mouse model (CR2-TAg) of metastatic prostate cancer arising in the neuroendocrine (NE) cell lineage. Biomarkers of NE differentiation in this model are expressed in conventional adenocarcinoma of the prostate with NE features. To further characterize the pathways that control NE proliferation, differentiation, and survival, we established prostate NE cancer (PNEC) cell lines from CR2-TAg prostate tumors and metastases. GeneChip analyses of cell lines harvested at different passages, and as xenografted tumors, indicated that PNECs express consistent features ex vivo and in vivo and share a remarkable degree of similarity with primary CR2-TAg prostate NE tumors. PNECs express mAsh1, a basic helix-loop-helix (bHLH) transcription factor essential for NE cell differentiation in other tissues. RNA interference knockdown of mAsh1, GeneChip comparisons of treated and control cell populations, and a computational analysis of down-regulated genes identified 12 transcriptional motifs enriched in the gene set. Affected genes, including Adcy9, Hes6, Iapp1, Ndrg4, c-Myb, and Mesdc2, are enriched for a palindromic E-box motif, CAGCTG, indicating that it is a physiologically relevant mAsh1 binding site. The enrichment of a c-Myb binding site and the finding that c-Myb is down-regulated by mAsh1 RNA interference suggest that mAsh1 and c-Myb are in the same signaling pathway. Our data indicate that mAsh1 negatively regulates the cell cycle (e.g., via enhanced Cdkn2d, Bub1 expression), promotes differentiation (e.g., through effects on cAMP), and enhances survival by inhibiting apoptosis. PNEC cell lines should be generally useful for genetic and͞or pharmacologic studies of the regulation of NE cell proliferation, differentiation, and tumorigenesis.neuroendocrine cell biology ͉ mouse prostate neuroendocrine cancer cell lines ͉ mAsh1 ͉ functional genomics ͉ phylogenetic footprinting T he prostate is a tubuloaveolar gland lined with a slowly renewing epithelium composed of three cell lineages. Secretory luminal cells predominate. Lineage progenitors appear to reside in a basal cell layer underlying luminal cells. A small population of scattered neuroendocrine (NE) cells produce dendrite-like processes that extend over several cell diameters to contact members of the other two epithelial lineages. Although they export a number of neuropeptides (1-3), the precise role played by NE cells in normal prostate physiology remains unclear.Pure NE tumors of the prostate are rare but, like most NE cell cancers, are very aggressive. Conventional adenocarcinoma of the human prostate (CaP) can display features of focal NE differentiation (NED) even when initiation does not occur in NE cells. The reported frequency of NED in CaP ranges from 30% to 100% depending on the study design and the biomarker panel used to define the phenotype (4-6). Recent findings indicate that NED correlates with poor prognosis and androgen-independent growth (7-9).The mechanisms governing development of NED in CaP are obscur...

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Section: Genechip Analysis Of Genes Regulated By Rnai Knockdown Of Mamentioning

confidence: 99%

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Wang²,

Stormo³

et al. 2004

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

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“…The B-cells also co-store islet amyloid polypeptide (IAPP or amylin) (Westermark et al 1986). During fetal development of the pancreas, endocrine cells are believed to differentiate from progenitor cells, forming clusters close to the ducts (Yamaoka & Itakura 1999).…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor II in human fetal pancreas and its co-localization with the major islet hormones: comparison with adult pancreas

Portela-Gomes

Höög²

2000

Journal of Endocrinology

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Insulin-like growth factor II (IGF-II) appears to play an important role during fetal life in cell growth and differentiation in several organs, including the pancreas.In the present study we investigated the cellular localization of IGF-II in human fetal pancreas at 16, 18 and 22 embryonic weeks and compared it with adult pancreas. Single and double immunofluorescence methods were used to study co-localization of IGF-II with the four major islet hormones -insulin, glucagon, somatostatin, pancreatic polypeptide -and with islet amyloid polypeptide (IAPP).Distinct IGF-II immunoreactive (IR) cells were found in the endocrine, but not in the exocrine, pancreas. The intensity of IGF-II immunoreactivity was more pronounced in the fetal than in the adult pancreas. In fetal pancreas IGF-II immunoreactivity was observed in virtually all insulin-IR cells and in subsets of the glucagon, somatostatin and IAPP cells. In the adult pancreas, IGF-II immunoreactivity was found in insulin/IAPP cells only.Our results suggest a broader effect of IGF-II in fetal endocrine pancreatic cells than in the adult.

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“…In over 50% of insulinomas investigated, amyloid deposits have been demonstrated (2)(3)(4). The major protein component of these deposits was identified as islet amyloid polypeptide (IAPP) (5,6). A peptide with the same amino acid (aa) sequence was purified from pancreatic islet amyloid in patients with type 2 (non-insulin-dependent) diabetes mellitus (7) and was named amylin (8).…”

Section: Introductionmentioning

confidence: 99%

Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation

Hulst¹,

Oosterwijk²,

Born

et al. 1999

European Journal of Endocrinology

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Objective: Islet amyloid polypeptide (IAPP), also named amylin, is the predominant protein component of amyloid deposits in human islet b cell tumours of the pancreas (insulinomas). IAPP is co-produced with insulin by islet b cells. We investigated IAPP expression in relation to insulin expression and to amyloid formation in eleven insulinomas. Design and methods: RNA and protein extracts were prepared from the same pieces of tumour tissue, and from specimens of two normal human pancreata. IAPP and insulin mRNA and peptide content were quantified using Northern blot analysis and radioimmunoassay (RIA) respectively. Molecular forms of IAPP immunoreactivity were analysed by reversed-phase high-performance liquid chromatography (HPLC). The presence of islet hormones and of amyloid was assessed by (immuno)histochemical staining of paraffin sections. Plasma levels of IAPP and insulin prior to tumour resection were determined by RIA. Results: IAPP and insulin mRNA and peptide content varied widely between the tumour specimens, and there was considerable intratumour heterogeneity of peptide content. HPLC analysis indicated correct proteolytic processing of the IAPP precursor protein. Amyloid deposits were detected only in the three tumours with the highest IAPP content. In contrast to insulin, plasma levels of IAPP were not elevated in the insulinoma patients. Conclusions: The spectrum of hormone production by insulinomas cannot be inferred from only a few tissue sections due to intratumour heterogeneity. Expression of the IAPP and insulin genes is not coupled in insulinomas, which produce properly processed mature IAPP. In addition to IAPP overproduction, additional factors such as intracellular accumulation of IAPP are involved in amyloidogenesis in insulinomas.

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A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas

Cited by 469 publications

References 20 publications

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Insulin-like growth factor II in human fetal pancreas and its co-localization with the major islet hormones: comparison with adult pancreas

Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation

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