Isolation and characterization of a tumor-derived human pancreastatin-related protein

Funakoshi, Susumu; Tamamura, Hirokazu; Ohta, Mitsuhiro; Yoshizawa, Kumi; Funakoshi, Akihiro; Miyasaka, Kyoko; Tateishi, Kensuke; Tatemoto, Kazuhiko; Nakano, Itsuro; Yajima, Haruaki; Fujii, Nobutaka

doi:10.1016/0006-291x(89)91694-x

Cited by 29 publications

(10 citation statements)

References 16 publications

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“…Possibly, the 3 cells process CGA very actively, generating high amounts of CST, while a cells may process CGA at a lower rate, leaving higher amounts of the intact precursor in secretory granules. (16) and high levels of PST (17) in human insulinoma tissues. Recently, f3-granin, a fragment of CGA, has been identified in rat insulinoma tissues (15) and it was localized immunohistochemically in insulinoma cells and in all islet cells of the rat (41).…”

Section: Resultsmentioning

confidence: 94%

“…Here we investigated the cellular distribution of CST, PST, and CGA in the adrenal medulla and endocrine pancreas, two organs known to contain CGA and various related peptides (10)(11)(12)(13)(14)(15)(16)(17). Chromaffin cells were strongly immunoreactive for CGA but contained no immunoreactivities for CST and PST.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies demonstrated that pancreatic islet cells and islet cell tumors contain various CGA-derived peptides (10)(11)(12)(13)(14)(15)(16)(17). In the human pancreas, CGA has been localized mainly to glucagon (a) cells (18).…”

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confidence: 99%

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Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

Cetin¹,

Aunis²,

Bader³

et al. 1993

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

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Chromogranin A (CGA) is a secretory protein present in the adrenal medulla and in a variety ofendocrine organs. This protein may serve as precursor for pancreastatin (PST) and for other biologically active peptides. Recently, chromostatin (CST), a CGA derivative, has been identified that possesses high biological activity. The cellular distribution of CST in various endocrine organs is completely unknown. Using immunohistochemistry on plastic sections, we investigated the occurrence and cellular distribution of CST, PST, and CGA in human endocrine pancreas of healthy and diseased states and in the adrenal medulla. In the normal and diabetic pancreas, CST immunoreactivity was localized exclusively in 13 cells, which were mostly unreactive for PST and CGA. Both latter peptides were confined mainly to glucagon (a) cells. Insulinoma cells displayed strong insulin, PST, and CGA immunoreactivities, but they were faintly immunoreactive for CST or unreactive. Adrenal chromaffm cells exhibited strong immunoreactivity for CGA but lacked CST and PST immunoreactivities. Based on the peculiar distributive pattern of CST, PST, and CGA, we suggest that CGA is differentially processed in chromaffin and islet tissues and in insulinoma cells. The unique cellular localization of CST in the endocrine pancreas ofnormal and pathological conditions may indicate that CST is involved in 13-cell function.Chromogranin A (CGA) is an acidic glycoprotein originally detected in the adrenal medulla but more recently found also in a variety of peptide hormone-producing cells (see refs. 1 and 2 for review). Despite its widespread distribution, the physiological function of CGA is still largely unknown.The primary amino acid sequence of CGA, elucidated by cDNA analysis, includes several pairs of basic residues, which by analogy with other peptide hormone precursors constitute potential sites of proteolytic cleavage (3-5). Thus, it was speculated that CGA may be a putative precursor of biologically active peptides (2, 6, 7). Pancreastatin (PST), a peptide fully contained in the porcine CGA sequence (3, 7), was isolated from the porcine pancreas (8). This peptide inhibits insulin secretion (8). Moreover, tryptic digestion of CGA yielded various peptides that were able to modulate catecholamine secretion (7). Recently, chromostatin (CST) has been identified as a CGA derivative, which is localized between amino acids 124 and 143 in the bovine CGA sequence (9). In contrast to PST, CST had potent inhibitory action on chromaffin cell secretion (9).Previous studies demonstrated that pancreatic islet cells and islet cell tumors contain various CGA-derived peptides (10)(11)(12)(13)(14)(15)(16)(17). In the human pancreas, CGA has been localized mainly to glucagon (a) cells (18). The cellular distribution of PST, however, is still a matter of controversy (see ref. 19 for review), which in part may be due to species specificities (20). Data on tissue distribution of CST are completely lacking.Using specific antisera against CST, PST, and CGA, we inves...

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

Cetin¹,

Aunis²,

Bader³

et al. 1993

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

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“…The lack of a high degree of conservation of the pancreastatin sequence poses a major difficulty in assigning physiological function to the peptide. Additional pancreastatin-like peptides have been isolated from human tumours and these comprise CgA residues 273-301, 254-301, 210-301 and 116-301 [27][28][29][30]. A C-terminally extended form of pancreastatin, corresponding to CgA residues 248-313, has also been isolated from bovine adrenal chromaffin cells [31].…”

Section: Introductionmentioning

confidence: 99%

The spectrum of endogenous human chromogranin A-derived peptides identified using a modified proteomic strategy

Orr¹,

Chen²,

Johnsen

et al. 2002

Proteomics

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The hypothesis that chromogranin A (CgA), a protein of neuroendocrine cell secretory granules, may be a precursor of biologically active peptides, rests on observed activities of peptide fragments largely produced by exogenous protease digestion of the bovine protein. Here we have adopted a modified proteomic strategy to isolate and characterise human CgA-derived peptides produced by endogenous prohormone convertases. Initial focus was on an insulinoma as previous studies have shown that CgA is rapidly processed in pancreatic beta cells and that tumours arising from these express appropriate prohormone convertases. Eleven novel peptides were identified arising from processing at both monobasic and dibasic sites and processing was most evident in the C-terminal domain of the protein. Some of these peptides were identified in endocrine tumours, such as mid-gut carcinoid and phaeochromocytoma, which arise from endocrine cells of different phenotype and in different anatomical sites. Two of the most interesting peptides, GR-44 and ER-37, representing the C-terminal region of CgA, were found to be amidated. These data would imply that the intact protein is C-terminally amidated and that these peptides are probably biologically active. The spectrum of novel CgA-derived peptides, described in the present study, should provide a basis for biological evaluation of authentic entities.

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“…In the present study, we could not observe any inhibitory effect when a 10 times higher dose of pancreastatin without a C-terminal amide was applied, whereas 100 pmol/kg per h of pancreastatin with a C-terminal amide could elicit an inhibitory effect on the pancreatic exocrine secretion. Therefore, we propose that pancreastatin acquires its inhibitory bioactivity on the exocrine pancreas by proteolytic processing of chromogranin A and amidation of the carboxy-terminal of pancreastatin [10].…”

Section: Discussionmentioning

confidence: 99%

The importance of the C‐terminal amide structure of rat pancreastatin to inhibit pancreatic exocrine secretion

et al. 1990

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A C-terminal fragment of rat pancreastatin, a 26 residue peptide amide and a fragment without a C-terminal amide were synthesized by Fmoc-based solid phase methods and their biological activities were compared. The rat C-terminal fragment inhibited pancreatic exocrine secretions produced by the intravenous injection of 2-deoxy-D-glucose (a central vagal nerve stimulation), whereas the fragment without a C-terminal amide showed no effect on pancreas. These results indicate that the C-terminal amide of this peptide is necessary to reveal its biological activity.

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Isolation and characterization of a tumor-derived human pancreastatin-related protein

Cited by 29 publications

References 16 publications

Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

The spectrum of endogenous human chromogranin A-derived peptides identified using a modified proteomic strategy

The importance of the C‐terminal amide structure of rat pancreastatin to inhibit pancreatic exocrine secretion

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