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BMC Genomics ; 15: 1074, 2014 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-25480530


BACKGROUND: Understanding the evolution of the vertebrate pancreas is key to understanding its functions. The chondrichthyes (cartilaginous fish such as sharks and rays) have often been suggested to possess the most ancient example of a distinct pancreas with both hormonal (endocrine) and digestive (exocrine) roles. The lack of genetic, genomic and transcriptomic data for cartilaginous fish has hindered a more thorough understanding of the molecular-level functions of the chondrichthyan pancreas, particularly with respect to their "unusual" energy metabolism (where ketone bodies and amino acids are the main oxidative fuel source) and their paradoxical ability to both maintain stable blood glucose levels and tolerate extensive periods of hypoglycemia. In order to shed light on some of these processes, we carried out the first large-scale comparative transcriptomic survey of multiple cartilaginous fish tissues: the pancreas, brain and liver of the lesser spotted catshark, Scyliorhinus canicula. RESULTS: We generated a mutli-tissue assembly comprising 86,006 contigs, of which 44,794 were assigned to a particular tissue or combination of tissues based on mapping of sequencing reads. We have characterised transcripts encoding genes involved in insulin regulation, glucose sensing, transcriptional regulation, signaling and digestion, as well as many peptide hormone precursors and their receptors for the first time. Comparisons to mammalian pancreas transcriptomes reveals that mechanisms of glucose sensing and insulin regulation used to establish and maintain a stable internal environment are conserved across jawed vertebrates and likely pre-date the vertebrate radiation. Conservation of pancreatic hormones and genes encoding digestive proteins support the single, early evolution of a distinct pancreatic gland with endocrine and exocrine functions in jawed vertebrates. In addition, we demonstrate that chondrichthyes lack pancreatic polypeptide (PP) and that reports of PP in the literature are likely due cross-reaction with PYY and/or NPY in the pancreas. A three hormone islet organ is therefore the ancestral jawed vertebrate condition, later elaborated upon only in the tetrapod lineage. CONCLUSIONS: The cartilaginous fish are a great untapped resource for the reconstruction of patterns and processes of vertebrate evolution and new approaches such as those described in this paper will greatly facilitate their incorporation into the rank of "model organism".

Encéfalo/metabolismo , Cação (Peixe)/genética , Cação (Peixe)/fisiologia , Perfilação da Expressão Gênica , Fígado/metabolismo , Pâncreas/fisiologia , Sequência de Aminoácidos , Animais , Digestão/genética , Evolução Molecular , Genes Homeobox/genética , Glucose/metabolismo , Insulina/química , Insulina/genética , Insulina/metabolismo , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Especificidade de Órgãos , Pâncreas/citologia , Pâncreas/metabolismo , Receptores de Hormônios Pancreáticos/genética , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo
Neurosci Lett ; 341(2): 131-4, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12686383


The pancreatic peptide hormone amylin (AMY) and the AMY receptor agonist salmon calcitonin (sCT) reduce short-term food intake in rats primarily by activating neurons located in the circumventricular area postrema. In the present study we analyzed the involvement of (an)orexigenic neuropeptides expressed in the lateral hypothalamic area (LHA) and in the arcuate nucleus in mediating the AMY and sCT-induced suppression of food intake. By using semiquantitative in situ hybridization 120 min after intraperitoneal injection of AMY or sCT (50 microgram/kg), orexin mRNA levels were decreased in LHA by AMY or sCT treatment. Moreover, sCT significantly suppressed the orexigenic melanin concentrating hormone in LHA, whereas mRNA levels of neuropeptide Y, cocaine and amphetamine regulated transcript, agouti-gene-related protein and proopiomelanocortin were unaffected by either treatment. In conclusion, the anorexigenic effect of AMY/sCT might be mediated by the observed reduced expression of orexigenic neuropeptides in the LHA.

Amiloide/farmacologia , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Calcitonina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Neuropeptídeos/genética , Proteína Relacionada com Agouti , Animais , Antiulcerosos/farmacologia , Núcleo Arqueado do Hipotálamo/metabolismo , Autorradiografia/métodos , Proteínas de Transporte/genética , Ingestão de Alimentos/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/genética , Hibridização In Situ/métodos , Peptídeos e Proteínas de Sinalização Intercelular , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Melaninas/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeos/metabolismo , Sondas de Oligonucleotídeos , Receptores de Orexina , Orexinas , Fragmentos de Peptídeos/farmacologia , Hormônios Hipofisários/genética , Pró-Opiomelanocortina/genética , Proteínas/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G , Receptores de Neuropeptídeos , Receptores de Hormônios Pancreáticos/antagonistas & inibidores , Salmão
Biochem Pharmacol ; 63(6): 1177-81, 2002 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11931851


The effects of the 17beta-estradiol, dihydrotestosterone and hormone antagonists tamoxifen and bicalutamide on telomerase activity and expression of cell cycle related proteins in the androgen-sensitive prostatic cancer cell line LNCaP were studied. The cell line was grown in RPMI supplemented with 2.5% charcoal-stripped FBS for 72 hr. The IC(50) of tamoxifen and bicalutamide and the optimal stimulatory concentrations of 17beta-estradiol and dihydrotestosterone were determined by means of the cell-viability assay, the activity of telomerase was measured by the telomere repeat amplification protocol (TRAP) and the expression of proteins was analysed by the Western blot technique. 17beta-estradiol stimulated cell growth more effectively than dihydrotestosterone whereas hormone antagonists tamoxifen and bicalutamide caused a significant decrease in cell viability. The treatment of cells by a combination of low doses of 17 beta-estradiol and dihydrotestosterone stimulated cells stronger than treatment by a single hormone. Only 17beta-estradiol, in concentration of 10nM, increased strongly the expression of p21(Waf1/Cip1) and increased slightly telomerase activity in the LNCaP cells. 50 microM of bicalutamide down-regulated the levels of the androgen receptor, the proliferating cell nuclear antigen and telomerase activity, and up-regulated the expression of p27(Kip1). We hereby describe the first observation of the influence of bicalutamide on telomerase activity and a positive correlation between the effect of 17beta-estradiol and the induction of both the endogenous cyclin-dependent kinase inhibitor, p21(Waf1/Cip1), and telomerase activity in a prostatic cancer cell line LNCaP. These findings can shed a new light on the steroid-signaling pathway in prostate cancer cells.

Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Neoplasias da Próstata/enzimologia , Receptores de Hormônios Pancreáticos/antagonistas & inibidores , Telomerase/metabolismo , Androgênios/metabolismo , Antineoplásicos Hormonais/farmacologia , Humanos , Immunoblotting , Ligantes , Masculino , Neoplasias da Próstata/patologia , Tamoxifeno/farmacologia , Telomerase/efeitos dos fármacos , Células Tumorais Cultivadas
Peptides ; 18(3): 397-401, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9145427


Cloned receptors for the PP-fold peptides are subdivided into Y1, Y2, PP1/Y4, Y5 and Y6. NPY and PYY have similar affinity for Y1, Y2, Y5 and Y6 receptors while PP has highest affinity for PP1. Pro34-substituted analogs of NPY and PYY have selectivity for Y1 and Y1-like receptors over Y2 receptors. In the present study, we found the putative Y1-selective radioligand, [125I]Leu31, Pro34-PYY, also binds with high affinity to the rat PP1 receptor in cell lines expressing the receptor. However, in rat brain sections, [125I]Leu31, Pro34-PYY does not appear to bind to the interpeduncular nucleus, a brain region containing a high density of [125I]-bPP binding sites. Therefore, it appears there is additional heterogeneity in receptors recognizing PP.

Hormônios Gastrointestinais/metabolismo , Neuropeptídeo Y/análogos & derivados , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Hormônios Pancreáticos/metabolismo , Animais , Encéfalo/metabolismo , Células CHO , Cricetinae , Radioisótopos do Iodo , Ligantes , Neuropeptídeo Y/química , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/fisiologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ratos , Receptores de Neuropeptídeo Y/química , Receptores de Hormônios Pancreáticos/química , Proteínas Recombinantes
Diabetes ; 45(2): 257-61, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8549871


Rat pancreatic alpha- and beta-cells are critically dependent on hormonal signals generating cyclic AMP (cAMP) as a synergistic messenger for nutrient-induced hormone release. Several peptides of the glucagon-secretin family have been proposed as physiological ligands for cAMP production in beta-cells, but their relative importance for islet function is still unknown. The present study shows expression at the RNA level in beta-cells of receptors for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide I(7-36) amide (GLP-I), while RNA from islet alpha-cells hybridized only with GIP receptor cDNA. Western blots confirmed that GLP-I receptors were expressed in beta-cells and not in alpha-cells. Receptor activity, measured as cellular cAMP production after exposing islet beta-cells for 15 min to a range of peptide concentrations, was already detected using 10 pmol/l GLP-I and 50 pmol/l GIP but required 1 nmol/l glucagon. EC50 values of GLP-I- and GIP-induced cAMP formation were comparable (0.2 nmol/l) and 45-fold lower than the EC50 of glucagon (9 nmol/l). Maximal stimulation of cAMP production was comparable for the three peptides. In purified alpha-cells, 1 nmol/l GLP-I failed to increase cAMP levels, while 10 pmol/l to 10 nmol/l GIP exerted similar stimulatory effects as in beta-cells. In conclusion, these data show that stimulation of glucagon, GLP-I, and GIP receptors in rat beta-cells causes cAMP production required for insulin release, while adenylate cyclase in alpha-cells is positively regulated by GIP.

Polipeptídeo Inibidor Gástrico/metabolismo , Glucagon/metabolismo , Fragmentos de Peptídeos/metabolismo , Precursores de Proteínas/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Glucagon/metabolismo , Receptores de Hormônios Pancreáticos/metabolismo , Adenilil Ciclases/metabolismo , Animais , AMP Cíclico/metabolismo , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Ilhotas Pancreáticas/metabolismo , Masculino , RNA Mensageiro/genética , Ratos , Ratos Wistar , Transdução de Sinais