A novel germline mutation in Peroxisome Proliferator-Activated Receptor γ gene associated with large intestine polyp formation and dyslipidemia
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A novel germline mutation in Peroxisome Proliferator-Activated Receptor γ gene associated with large intestine polyp formation and dyslipidemia (105 visite)

Capaccio D, Ciccodicola A, Sabatino L, Casamassimi A, Pancione M, Fucci A, Febbraro, Merlino A, Graziano G, Colantuoni V

Biochim Biophys Acta (ISSN: 0925-4439, 0006-3002, 1570-9639), 2010; 1802(6): 572-581.



Tipo di articolo: Journal Article,

Impact factor: 2.773, Impact factor a 5 anni: 2.751

Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-77952240564&partnerID=40&md5=f0a185472554530c6ce54fec0f6a1265

Parole chiave: Colorectal Cancer, Dyslipidemia, Loss-Of-Function Mutation, Peroxisome Proliferator-Activated Receptor, High Density Lipoprotein Cholesterol, Insulin, Low Density Lipoprotein Cholesterol, Peroxisome Proliferator Activated Receptor Gamma, Triacylglycerol, Adult, Aged, Amino Acid Substitution, Article, Cancer Localization, Cell Proliferation, Cholesterol Blood Level, Clinical Article, Colon Carcinogenesis, Colon Polyp, Colonoscopy, Controlled Study, Female, Gene Mutation, Genetic Association, Germ Line, Glucose Blood Level, Histopathology, Human, Human Cell, Human Tissue, Hypertension, In Vitro Study, In Vivo Study, Insulin Blood Level, Ligand Binding, Lipid Metabolism, Liver Metastasis, Loss Of Function Mutation, Non Insulin Dependent Diabetes Mellitus, Nucleotide Sequence, Obesity, Priority Journal, Protein Expression, Protein Function, Triacylglycerol Blood Level, Wild Type, Adenocarcinoma, Adolescent, 80 And Over, Animals, Base Sequence, Binding Sites, Cercopithecus Aethiops, Colonic Neoplasms, Cos Cells, Dna Primers, Germ-Line Mutation, Intestinal Polyps, Loss Of Heterozygosity, Middle Aged, Models, Molecular, Nih 3t3 Cells, Pedigree, Ppar Gamma, Recombinant Proteins, Transfection, Young Adult,

Affiliazioni:

*** IBB - CNR ***
Department of Biological and Environmental Sciences, University of Sannio, Via Port'Arsa, 11, 82100 Benevento, Italy
Institute of Genetics and Biophysics, A. Buzzati-Traverso CNR, Via P. Castellino, 113, 80131 Napoli, Italy
Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini, 5, 80131 Napoli, Italy
Fatebenefratelli Hospital, Division of Medical Oncology, Viale Principe di Napoli, 82100 Benevento, Italy
Department of Chemistry, University of Naples Federico II, Monte S. Angelo, 80100 Napoli, Italy


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Spiegelman, B. M., PPAR: adipogenic regulator and thiazolidinedione receptor (1998) Diabetes, 47, pp. 507-514

Feige, J. N., Gelman, L., Michalik, L., Desvergne, B., Wahli, W., From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions (2006) Prog. Lipid Res., 45, pp. 120-159

Willson, T. M., Lambert, M. H., Kliewer, S. A., Peroxisome proliferator-activated receptor and metabolic disease (2001) Annu. Rev. Biochem., 70, pp. 341-367

Savage, D. B., Tan, G. D., Acerini, C. L., Jebb, S. A., Agostini, M., Gurnell, M., Williams, R. L., O'Rahilly, S., Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor (2003) Diabetes, 52, pp. 910-917

Peverali, F. A., Ramqvist, T., Saffrich, R., Pepperkok, R., Barone, M. V., Philipson, L., Regulation of G1 progression by E2A and Id helix-loop-helix proteins (1994) EMBO J., 13, pp. 4291-4301

Barone, M. V., Courtneidge, S. A., Myc but not Fos rescue of PDGF signaling block caused by kinase-inactive Src (1995) Nature, 378, pp. 509-512

Yeh, J. J., Marsh, D. J., Zedenius, J., Dwight, T., Delbridge, L., Robinson, B. G., Eng, C., Fine-structure deletion mapping of 10q22-24 identifies regions of loss of heterozygosity and suggests that sporadic follicular thyroid adenomas and follicular thyroid carcinomas develop along distinct neoplastic pathways (1999) Genes Chromosomes Cancer, 26, pp. 322-328

Kinzler, K. W., Vogelstein, B., Lessons from hereditary colorectal cancer (1996) Cell, 87, pp. 159-170

Gupta, R. A., Sarraf, P., Mueller, E., Brockman, J. A., Prusakiewicz, J. J., Eng, C., Willson, T. M., DuBois, R. N., Peroxisome proliferator-activated receptor mediated differentiation: a mutation in colon cancer cells reveals divergent and cell type-specific mechanisms (2003) J. Biol. Chem., 278, pp. 22669-22677

Girnun, G. D., Smith, W. M., Drori, S., Sarraf, P., Mueller, E., Eng, C., Nambiar, P., Spiegelman, B. M., APC-dependent suppression of colon carcinogenesis by PPAR (2002) Proc. Natl. Acad. Sci. U. S. A., 99, pp. 13771-13776

Teresi, R. E., Shaiu, C. W., Chen, C. S., Chatterjee, V. K., Waite, K. A., Eng, C., Increased PTEN expression due to transcriptional activation of PPAR by lovastatin and rosiglitazone (2006) Int. J. Cancer, 118, pp. 2390-2398

Annicotte, J. S., Iankova, I., Miard, S., Fritz, V., Sarruf, D., Abella, A., Berthe, M. L., Iborra, F., Peroxisome proliferator-activated receptor regulates E-cadherin expression and inhibits growth and invasion of prostate cancer (2006) Mol. Cell. Biol., 26, pp. 7561-7574

Iatropoulos, M. J., Williams, G. M., Proliferation markers (1996) Exp. Toxicol. Pathol., 48, pp. 175-181

Platt, A. M., Mowat, A. M., Mucosal macrophages and the regulation of immune responses in the intestine (2008) Immunol. Lett., 119, pp. 22-31

Gampe, R. T., Montana, V. G., Lambert, M. H., Miller, A. B., Bledsoe, R. K., Milburn, M. V., Kliever, S. A., Xu, E. H., Asymmetry in the PPAR /RXR crystal structure reveals the molecular basis of heterodimerization among nuclear receptors (2000) Mol. Cell, 5, pp. 545-555

Petersen, M. T., Jonson, P. H., Petersen, S. B., Amino acid neighbours and detailed conformational analysis of cysteines in proteins (1999) Protein Eng., 12, pp. 535-548

Kraulis, P. J., MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures (1991) J. Appl. Crystallogr., 24, pp. 946-950

Tsai, Y. S., Kim, H. J., Takahashi, N., Kim, H. S., Hagaman, J. R., Kim, J. K., Maeda, N., Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPAR (2004) J. Clin. Invest, 114, pp. 163-175



We report a novel PPARG germline mutation in a patient affected by colorectal cancer that replaces serine 289 with cysteine in the mature protein (S289C). The mutant has impaired transactivation potential and acts as dominant negative to the wild type receptor. In addition, it no longer restrains cell proliferation both in vitro and in vivo. Interestingly, the S289C mutant poorly activates target genes and interferes with the inflammatory pathway in tumor tissues and proximal normal mucosa. Consistently, only mutation carriers exhibit colonic lesions that can evolve to dysplastic polyps. The proband presented also dyslipidemia, hypertension and overweight, not associated to type 2 diabetes; of note, family members tested positive for the mutation and display only a dyslipidemic profile at variable penetrance with other biochemical parameters in the normal range. Finally, superimposing the mutation to the crystal structure of the ligand binding domain, the new Cys289 becomes so closely positioned to Cys285 to form an S-S bridge. This would reduce the depth of the ligand binding pocket and impede agonist positioning, explaining the biological effects and subcellular distribution of the mutant protein. This is the first PPARG germline mutation associated with dyslipidemia and colonic polyp formation that can progress to full-blown adenocarcinoma. © 2010 Elsevier B.V.
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* Relevance of the amino acid conversions L144R (Zaragoza) and L159P (Zavalla) in the apolipoprotein A-I binding site for haptoglobin (111 visite)
Biol Chem Biological Chemistry (ISSN: 1431-6730, 1437-4315), 2008 Nov; 389(11): 1421-1426.
Impact Factor: 3.035
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Salvatore B, Simeone R, Fonti R, Marciano R, Bianco R, Damiano V, Tortora G, Pace L, Del Vecchio S, Salvatore M
* 18F-FDG PET/CT in the assessment of early response to chemotherapy and molecularly targeted agents in metastatic colorectal cancer (91 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2008 Oct; 35: N/D-N/D.
Impact Factor: 4.532
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Vettor R, Granzotto M, De Stefani D, Trevellin E, Rossato M, Farina MG, Milan G, Pilon C, Nigro A, Federspil G, Vigneri R, Vitiello L, Rizzuto R, Baratta R, Frittitta L
* Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization (110 visite)
Journal Of Clinical Endocrinology & Metabolism (ISSN: 0021-972x), 2008 Sep; 93(9): 3541-3550.
Impact Factor: 6.325
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De Simone G, Di Fiore A, Supuran CT
* Are carbonic anhydrase inhibitors suitable for obtaining antiobesity drugs? (122 visite)
Curr Pharm Des Current Pharmaceutical Design (ISSN: 1381-6128, 1873-4286), 2008 Mar; 14(7): 655-660.
Impact Factor: 4.399
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Mainenti PP, Cirillo LC, Camera L, Persico F, Cantalupo T, Pace L, De Palma GD, Persico G, Salvatore M
* Accuracy of single phase contrast enhanced multidetector CT colonography in the preoperative staging of colo-rectal cancer (108 visite)
Eur J Radiol (ISSN: 0720-048x), 2006 Dec; 60(3): 453-459.
Impact Factor: 1.332
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Caprio MG, Cantalupo T, Mainenti PP, Mainolfi CG, Varrone A, Salvatore B, Persico F, D'Antonio D, Pace L, Salvatore M
* 18F-fdg pet, pet/ct and ce-mdct in locally advanced colorectal cancer (85 visite) (PDF 78 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2006 Sep; 33: N/D-N/D.
Impact Factor: 4.041
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Storto G, Mainenti PP, Varrone A, Mainolfi C, Salvatore B, Caprio MG, Cella L, Soricelli A, Pace L, Salvatore M
* Role of FDG-PET/CT in the staging of colorectal cancer (94 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2006 Sep; 33: N/D-N/D.
Impact Factor: 4.041
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Palmieri V, Storto G, Arezzi E, Pellegrino T, Mancini M, Di Minno G, Ferrara AL, Cuocolo A, Celentano A
* Relations of left ventricular mass and systolic function to endothelial function and coronary flow reserve in healthy, new discovered hypertensive subjects (113 visite)
J Hum Hypertens (ISSN: 0950-9240), 2005 Dec; 19(12): 941-950.
Impact Factor: 2.405
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Colao A, Di Somma C, Cuocolo A, Spinelli L, Acampa W, Spiezia S, Rota F, Savanelli MC, Lombardi G
* Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a two-year open, prospective study in young adult men and women with severe GH deficiency (122 visite)
J Clin Endocrinol Metab (ISSN: 0021-972x), 2005 Sep; 90(9): 5146-5155.
Impact Factor: 6.02
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Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, Manfioletti G, Barbetti F, Brunetti A, Croce CM, Fusco A, Brunetti A
* Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice (106 visite)
Nat Med (ISSN: 1078-8956, 0034-7264), 2005 Jul; 11(7): 765-773.
Impact Factor: 28.878
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Mainenti PP, Romano M, Imbriaco M, Camera L, Pace L, D'Antonio D, Bucci L, Galloro G, Salvatore M
* Added value of CT colonography after a positive conventional colonoscopy: Impact on treatment strategy (104 visite)
Abdom Imaging (ISSN: 0942-8925, 1432-0509), 2005 Jan; 30(1): 42-47.
Impact Factor: 1.034
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Giacco R, Clemente G, Luongo D, Lasorella G, Fiume I, Brouns F, Bornet F, Patti L, Cipriano P, Rivellese AA, Riccardi G
* Effects of short-chain fructo-oligosaccharides on glucose and lipid metabolism in mild hypercholesterolaemic individuals (134 visite)
Clin Nutr (ISSN: 0261-5614), 2004 Jun; 23(3): 331-340.
Impact Factor: 2.019
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Pauciullo P, Giannino A, De Michele M, Gentile M, Liguori R, Argiriou A, Carlotto A, Faccenda F, Mancini M, Bond MG, De Simone V, Rubba P
* Increased carotid artery intima-media thickness is associated with a novel mutation of low-density lipoprotein receptor independently of major cardiovascular risk factors (138 visite)
Metab Clin Exp (ISSN: 0026-0495, 1532-8600), 2003; 52(11): 1433-1438.
Impact Factor: 2.013
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Colao A, Di Somma C, Pivonello R, Cuocolo A, Spinelli L, Bonaduce D, Salvatore M, Lombardi G
* The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: A 12-month prospective study (122 visite)
J Clin Endocrinol Metab (ISSN: 0021-972x), 2002 Mar; 87(3): 1088-1093.
Impact Factor: 5.199
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Colao A, Di Somma C, Cuocolo A, Spinelli L, Tedesco N, Pivonello R, Bonaduce D, Salvatore M, Lombardi G
* Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients, with GH deficiency (123 visite)
J Clin Endocrinol Metab (ISSN: 0021-972x), 2001 May; 86(5): 1874-1881.
Impact Factor: 5.16
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Renda A, Iovino F, Capasso L, Ricciardelli L, Tammaro V, Acampa W
Radioimmunoguided surgery in colorectal cancer: A 6-year experience with four different technical solutions (95 visite)
Semin Surg Oncol Wiley Liss Inc (ISSN: 8756-0437), 1998 Dec; 15(4): 226-230.
Impact Factor: 1.045
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Marotta T, Ferrara LA, Di Marino L, Mancini M, Annuzzi G, Russo O, D'Orta G, Lucarelli C, Rossi F
Factors affecting lipoprotein lipase in hypertensive patients (90 visite)
Metab Clin Exp (ISSN: 0026-0495, 1532-8600), 1995 Jun; 44(6): 712-718.
Impact Factor: 1.681
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Alfano B, Coucourde F, Malgieri F, Ragozzino A
PET/CT and radiotherapy (142 visite)
Q J Nucl Med Mol Imaging, 1980 Oct; 50(1): 4-14.
Impact Factor: 0
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39 Records (35 escludendo Abstract e Conferenze).
Impact factor totale: 163.757 (146.612 escludendo Abstract e Conferenze).
Impact factor a 5 anni totale: 145.745 (127.4 escludendo Abstract e Conferenze).







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