Role of Gastrointestinal Hormones in the Proliferation of Normal and ...

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572 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationof the pancreas (7), pituitary (8), and extraantral G cells (9).Gastrin release is stimulated by food components, particularlyaromatic amino acids and amine derivatives of aminoacids, and is inhibited by luminal acid (10).Human progastrin, the precursor of gastrin, consists of a21-amino-acid signal peptide, a 37-amino-acid N-terminalextension, the gastrin-34 sequence, and a 9-amino-acid C-terminal extension (3, 10). In antral G cells, progastrin isstored and processed into secretory granules, and N-terminaland C-terminal extensions are removed by prohormone convertases.The C-terminal basic amino acids are sequentiallyremoved by a carboxypeptidase, which results in the formationof glycine-extended G34 (G34-gly). G34-gly is amidatedby peptidyl glycine -amidating monooxygenase toform G34-NH 2 (G-34) or cleaved at internal lysine/lysineresidues to form G-17-gly (referred to as G-gly) (10). Recentstudies have demonstrated that the majority of G-17-NH 2(also known as gastrin or G-17) arises from the conversion ofG34-NH 2 to G-17-NH 2 , rather than by amidation of G-gly,suggesting that the conversion of G-gly to amidated G-17 isblocked and that G-gly is a terminal, secondary end-productof progastrin processing in normal antral G cells (10, 11). Thisis contrasted by evidence in colon cancer cells that gastrinbypasses the processing machinery and is expressed inlarger, unprocessed forms that are transported in secretoryvesicles and continuously fused with the plasma membraneand released (11).2. CCK. CCK was described in 1928 by Ivy and Oldberg (12)as a contaminant in impure secretin preparations. These impuritieswere noted to produce gallbladder contraction indogs and cats. In 1943, Harper and Raper (13) identified asingle agent extracted from intestinal samples that possessedpancreatic-stimulating activity. After complete purificationand sequencing, it was determined that this single compound,CCK, was responsible for gallbladder contractionand pancreatic enzyme secretion (14). Other actions of CCKinclude inhibition of gastric emptying, stimulation of bowelmotility, potentiation of insulin secretion, and trophic effectson the pancreas and GI mucosa (3). CCK release is stimulatedby fats, proteins, and amino acids.CCK is produced by endocrine cells of the gut (primarilyduodenum and jejunum), the neurons of the brain, and theperipheral nervous system of the GI tract (15–18). Ultrastructuralstudies demonstrate that the cells are identical to I cellsof the human intestine (19). CCK neurons are found in themyenteric plexus, submucosal plexus, and circular musclelayers of the distal intestine and colon (9). PostganglionicCCK nerve fibers are found in the pancreas surrounding theislets of Langerhans (20). Furthermore, although CCK hasnot been found in the intrinsic neurons of the stomach andduodenum, CCK cells are in the celiac plexus and can befound in the vagus nerve, especially after injury (21, 22).The molecular forms of CCK are diverse and appear to betissue-specific (23, 24). The most abundant form in the brainappears to be CCK-8, although significant amounts of largercarboxy-amidated forms like CCK-33, CCK-58, and CCK-83have been isolated.3. BBS/GRP. BBS, a tetradecapeptide originally isolated fromthe skin of the frog Bombina bombina, is analogous to mammalianGRP (24). In general, BBS/GRP may be thought of asa universal on-switch with predominantly stimulatory effects.BBS/GRP stimulates the release of all GI hormones,intestinal and pancreatic secretion, and motility (24). Themost important functions of BBS/GRP are antral gastrinrelease and stimulation of gastric acid secretion (25, 26). Thispeptide also stimulates growth of the GI mucosa and pancreas(24).BBS/GRP-like immunoreactivity is widely distributedthroughout the GI tract of rats, guinea pigs, dogs, and humans(27–31), predominantly in the neuronal populations ofthe gut. GRP is most abundant in the stomach, with GRPpositivecells and fibers innervating the oxyntic and antralmucosa and circular muscle.4. NT. NT, a tridecapeptide originally isolated from bovinehypothalamus (32), is localized mainly in the central nervoussystem (predominantly hypothalamus and pituitary) and inendocrine cells (N cells) of the jejunal and ileal mucosa (33,34). NT is released in response to increased intraluminal fats(35, 36) and has numerous functions in the GI tract, includingstimulation of pancreatic secretion (37), inhibition of gastricand small bowel motility (38), facilitation of fatty acid translocationfrom the intestinal lumen (39), and growth stimulationof various GI tissues (34, 40–43).NT is produced from a single precursor, preproneurotensin,that contains both NT 1–13 and the related peptide,neuromedin N. Neuromedin N comprises the C-terminalportion of the proneurotensin peptide after NT is removed.NT 1–13, the major product of proneurotensin in the ileumand brain (44), is cleaved at or soon after secretion at thedibasic arg 8 -arg 9 residues, resulting in the inactive degradationproduct NT 1–8 and the biologically active NT 9–13.Substance P, muscarinic agonists (carbachol), catecholamines,and BBS/GRP stimulate NT release, suggesting that a complexinterplay of neural, endocrine, and luminal mechanisms is responsiblefor NT release and physiological functioning (45–47).5. PYY. PYY, a 36-amino-acid peptide, is homologous to twoother regulatory peptides, pancreatic polypeptide (PP) andneuropeptide Y (NPY) (3). Both the rat and human PYY geneshave been isolated and characterized (48, 49). The conservedstructural organization of the genes encoding PYY, NPY, andPP suggests that each gene is derived from duplication of acommon ancestral gene. The biological actions of PYY includeinhibition of pancreatic bicarbonate secretion and contractionof the gallbladder (50). In addition, PYY inhibitsgastric emptying and intestinal transit and has been postulatedas an agent that contributes to the ileal brake phenomenon,a negative-feedback mechanism that promotes intestinalabsorption (3). PYY can also stimulate growth of the GImucosa (51).PYY, NPY, and PP are synthesized as prepropeptides consistingof a signal peptide followed by the 36-residue activepeptide, a cleavage-sequence Gly-Lys-Arg, and a carboxyterminalflanking peptide (52, 53). During processing, theprecursor is cleaved at the carboxy terminal by a specificprohormone convertase. The Lys-Arg sequences are thenlysed by a carboxypeptidase, and the carboxy-terminal tyrosineis amidated. Typical enteroendocrine cells, with longDownloaded from edrv.endojournals.org by on July 16, 2007
Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 573basal processes, are visualized by immunohistochemistry inthe mucosa of the ileum, colon, and rectum (54).6. GLP. GLPs are a group of peptides known as the enteroglucagons.The enteroglucagons are products of the samegene that produces glucagon in the pancreatic -cell (3). Theintestinal L cell produces two elongated glucagons, glicentinand oxyntomodulin, and both of the enteroglucagons, GLP-1and GLP-2 (55). Both GLP-1 and GLP-2 have effects on nutrientabsorption and GI tract physiology; however, thesetwo peptides have distinct roles. GLP-1 has a significanteffect on blood glucose levels, lowering blood glucose levelsvia stimulation of insulin secretion (55), thus suggesting thatGLP-1 may provide some therapeutic benefit to patients withdiabetes. GLP-2 displays minimal effects on glucose levels,but demonstrates potent trophic effects on intestinal epithelia(55).Both GLP-1 and GLP-2 are released when the L cell isexposed luminally to the products of a mixed meal (carbohydrateor fat) (55). L cells are most abundant in the mucosaof the ileum and colon; they are the second most numerouspopulation of endocrine cells in the human intestine, afterenterochromaffin cells (56). Both GLP-1 and GLP-2 are rapidlycleaved by the exopeptidase dipeptidyl peptidase IV(55). Current concepts of L cell regulation involve integrationof hormonal messages from peptides, such as GRP and glucose-dependentinsulinotropic polypeptide, and neuronalcontrol (55).7. Somatostatin. Somatostatin was isolated and characterizedfrom ovine hypothalamic tissue during a search for a GHreleasingfactor (57). Since the identification and purificationof somatostation-14, precursor forms of greater molecularweight, including somatostatin-28, with somatostatin-14making up the C terminus, and larger precursor forms of 120or more amino acids have been identified (58). All of thesepeptides exert biological activity but differ in their relativepotency.Somatostatin has been detected in the nerves and cellbodies of the central and peripheral nervous systems, includingthe autonomic nervous system of the GI tract and theendocrine-like D cells of the pancreatic islets and mucosa ofthe stomach and intestine (3). More than 90% of the somatostatinimmunoreactivity in the human gut is located withinthe mucosal endocrine D cells (58). In addition, somatostatinis located in the nerves of the myenteric plexus. Somatostatinin the pancreas is located in the D cells at the periphery of theislets closely associated with the -cells (59).Somatostatin is a regulatory-inhibitory peptide, which, incontrast to BBS/GRP, may be considered as the universalendocrine off-switch. Somatostatin inhibits the release of GHand somatomedin C and all known GI hormones (3). Somatostatinalso inhibits gastric acid secretion and motility, intestinalabsorption, and pancreatic bicarbonate and enzymesecretion, and selectively decreases splanchnic and portalblood flow (60). In addition, somatostatin can inhibit thegrowth of normal and neoplastic tissues (61–67).B. GI hormone receptors and signal transduction pathways1. Receptors. GI hormone-stimulated signal transduction occurswith the binding of hormones to their cognate cell surfacereceptor, the G protein-coupled receptor (GPCR) (68).The GI hormone-GPCRs have the typical structural featuresof G protein binding seven-transmembrane receptors (Fig. 1).The receptors for gastrin, CCK, BBS/GRP, NT, PYY, GLP-2,and somatostatin, which are respectively, the gastrin/CCK-Breceptor, CCK-A receptor, GRP receptor, the NT receptor(NTR), NPY receptor, GLP-2 receptor, and the somatostatinreceptor (five subtypes), are all GPCRs (3, 55). GPCRs regulatea number of physiological processes, including proliferation,growth, and development (68). It was originallythought that, in order for GPCR signaling to occur, specificinteractions between the GI hormone and the receptor werenecessary to produce conformational changes in the receptorand stimulate intracellular signal transduction networks.However, recent studies suggest a more complex regulationof the GPCRs through: 1) dimerization with themselves andother receptors; 2) activation of differing G proteins; 3) internalizationand desensitization; and 4) ability to change inconformation and interactions with empty, or inactive, receptors(69). It is suggested that this complicated mechanismof regulation allows peptides to interact with GPCRs to stimulatediverse intracellular signaling pathways and ultimatelyaffect multiple physiological functions, depending on celltype.2. Signal transduction pathways. The seven transmembranespanning-helical domains function as ligand-regulatedguanine nucleotide exchange factors for the intracellular heterotrimericG proteins (68). Heterotrimeric G proteins arecomposed of the products of three gene families encoding -,-, and -subunits (68). The agonist-activated GPCR catalyzesthe exchange of GTP for GDP bound to the G-subunit,as well as the dissociation of the GTP-G from its cognateG dimer (Fig. 2A) (68). The activated GTP-G- and Gsubunits,in turn, regulate the activity of various intracellulareffector proteins such as phospholipases, adenylyl cyclases,protein kinases, membrane ion channels, and members of theRas family of GTP-binding proteins (68). In addition, basedon structural similarities, the 20 identified G-subunits havebeen divided into four subfamilies and assigned an effectorpathway based on current evidence. The four are: 1) thecholera toxin-sensitive () subunits that stimulate adenylcyclase and increase cAMP levels; 2) the pertussis toxinsensitive( i/o ) subunits that inhibit adenylyl cyclase activity;3) the pertussis toxin-insensitive ( q/11/14 ) subunits that stimulatemembrane phospholipases; and 4) the 12/13 subfamilythat links GPCR to the Ras-related GTP-binding protein, Rho(68). Additionally, 12 G- and 6-G subunits have been identified;these -dimers have been linked to the signalingmolecules phosphatidylinositol 3-kinase (PI3K) and selectforms of adenylyl cyclase and receptor kinases (68).Among the multiple intracellular signaling pathways thatmediate the proliferative effects of GPCRs, a family of relatedserine-threonine kinases, collectively known as ERKs orMAPKs, appear to play a central role (70). After phosphorylationby their immediate upstream MAPK kinase, membersof the MAPK family translocate to the nucleus, wherethey phosphorylate transcription factors, thus regulating theexpression of genes that control growth (71). Hormones actas ligands to eventually activate p42 and p44 MAPK (Fig. 2B)Downloaded from edrv.endojournals.org by on July 16, 2007
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