Chromatin enrichment of histone marks H4Ac and H3K9me3 in TP53 gene domain in breast cells

In non-cancerous breast cell lines HB2 and MCF10A the TP53 gene is localized inside a relatively small ~ 50 kb loop domain delimited by two S/MARs. Aim. To analyze the chromatin markers H4Ac and H3K9me3 of these two S/MARs and of the TP53 gene P1 promoter in different breast cells lines. Methods. We used chromatin immunoprecipitation (ChIP) to characterize the chromatin status of these S/MARs elements in breast non-cancerous cell lines HB2 and MCF10A and cancerous MCF-7, MDA-MB-231, BT-474 and T47D cell lines, by chromatin enrichment of H4Ac and H3K9me3 epigenetic markers, hallmarks of open and closed chromatin, respectively. Results. We found that these chromatin epigenetic markers are differentially distributed in S/MARs for all analyzed breast cell lines. Conclusions. We found no correlation between S/MARs and chromatin epige- netic status, suggesting that nuclear matrix fixation and chromatin status can be independent. High enrichment of H3K9me3 in the TP53 gene P1 promoter region in MCF-7, could explain lower levels of the TP53 expression, described earlier by our group.У неонкогенних клітинних лініях HB2 і MCF10A ген TP53 локалізований всередині відносно невеликої області (~ 50 тис. пар нуклеотидів) петлі домену, обмеженої двома S/MARs (ділянками, асо- ційованими з матриксом). Мета. Проаналізувати хроматинові маркери H4Ac і H3K9me3 в означених S/MARs і P1 промоторі гена TP53 в різних клітинних лініях молочної залози. Методи. Використано імунопреципітацію хроматину (чип) для характеристики стану хроматину елементів S/MARs у неонкогенних клітинних лініях HB2 і MCF10A та злоякісних клітинних лініях MCF-7, MDA-MB-231, БТ-474 і T47D за допомогою H4Ac і H3K9me3 епігенетичних маркерів за ознаками відкритого і закритого хроматину відповідно. Результати. Виявлено, що зазначені епігенетичні маркери нерівномірно розподілені в S/MARs для всіх проаналізованих клітинних ліній молочної залози. Висновки. Не знайдено кореляції в епігенетичному статусі S/MARs і хроматина, що дозволяє зробити припущення, що фіксація ядерного матриксу і статус хроматину можуть бути незалежними. Суттєве збагачення H3K9me3 P1 промоторної областігена TP53 в клітинній лінії MCF-7 може бути причиною нижчих рівнів експресії TP53, описаних раніше нашою групою.В неонкогенных клеточных линиях HB2 и MCF10A ген TP53 расположен внутри петли домена:относительно небольшой области (~ 50 тыс. пар нуклеотидов), ограниченной двумя S/MARs (участками, ассоциированными с матриксом). Цель. Проанализировать маркеры хроматина H4Ac и H3K9me3 в указанных S/MARs и P1 промотре гена TP53 в различных клеточных линиях молочной железы. Методы. Использовали иммунопреципитацию хроматина (чип) для характеристики состояния хроматина элементов S/MARs в неонкогенных клеточных линиях HB2 и MCF10A и злокачественных клеточных линиях MCF-7, MDA-MB-231, БТ-474 и T47D с помощью H4Ac и H3K9me3 эпигенетических маркеров по признакам открытого и закрытого хроматина соответственно. Результаты. Указанные эпигенетические маркеры неравномерно распределены в исследованных S/MARs для всех анализируемых линий клеток молочной железы. Выводы. Не выявлена корреляция в эпигенетическом статусе S/MARs и хроматина, что позволяет предположить, что фиксация в ядерного матрикса и статус хроматина могут быть независимыми. Существенное обогащение H3K9me3 P1 промоторной области гена TP53 клеточной линии MCF-7 может быть причиной более низких уровней экспрессии TP53, описанных ранее нашей группой

Mechanisms Of Esophageal Cancer Development In Brazilians

Esophageal cancer represents one of the most common and lethal cancers around the World. Some areas of South America, including parts of Brazil, present the highest incidence of the disease in the West. The main etiological factors that have been associated with the disease in Brazil are alcohol consumption, tobacco smoking and, in the South, consumption of hot maté. Nitrosamines are the only carcinogens capable of inducing tumors in the esophagus of experimental animals, with the rat being the most susceptible species, mainly due to tissue specific metabolic activation by CYP enzymes. Studies of CYP2A expression in the esophagus of rodents suggest an association between CYP2A expression and esophageal susceptibility to tumor induction. CYP2A6 and CYP2E1, the main enzymes to activate nitrosamines in humans, are the only carcinogen activating CYP enzymes to be expressed in the esophagus of Brazilians. Patients who presented high levels of CYP2A6 expression could activate nitrosamines at rates comparable to the rat. This expression profile is different from those present in French patients. We investigated 34 Brazilian patients regarding the risk associated with polymorphisms in drug metabolizing enzymes and TP53 mutations. A GSTP1 polymorphism presented a clear risk to white and non-white patients to develop esophageal cancer. GSTM1 null polymorphism also seemed to be associated with an increased risk. CYP2A6, CYP2E1, SOD2, and GSTT1 polymorphisms were not associated with an increased risk of esophageal cancer. TP53 mutations occurred mostly in exon 7, differing from the mutation profile found in the IARC database. The preliminary results obtained with polymorphisms of drug metabolizing enzymes and TP53 mutations need to be confirmed in a larger number of samples in order to compare the mechanisms of esophageal cancer development in Brazilians with that of other populations. © 2003 Elsevier B.V. All rights reserved.54402/03/15365373Parkin, D.M., Pisani, P., Ferlay, J., Estimates of the World wide incidence of the 25 major cancers in 1990 (1999) Int. J. Cancer, 80, pp. 827-841Allen, J.W., Richardson, J.D., Edwards, M.J., Squamous cell carcinoma of the esophagus: A review and update (1997) Surg. Oncol., 6, pp. 193-200Craddock, V.M., (1993) Cancer of the Esophagus, , Cambridge University Press, Cambridge, UKYang, C.S., Research on esophageal cancer in China: A review (1980) Cancer Res., 40, pp. 2633-2644Esophageal cancer studies in the caspian litoral of Iran: results of population study - a prodrome (1977) J. Natl. Cancer Inst., 59, pp. 1127-1138(2003), http://www.inca.gov.br, Brazilian Health Ministry, Estimativas da Incidência e Mortalidade por Câncer no Brasil, Instituto Nacional do Câncer (INCA), Ministério da SaúdeWaterhouse, J.A.H., Muir, K., Shanmugatnam, K., Powell, J., Cancer Incidence in the Five Continents, IV. , International Agency for Research on Cancer, Lyon, 1982Prolla, J.C., Dietz, J., Da Costa, L.A., Diferenças Geográficas na mortalidade por câncer de esôgfago no Rio Grande do Sul (1993) Rev. Ass. Med. Brasil., 39, pp. 217-220Corley, D.A., Buffler, P.A., Oesophageal and gastric cardia adenocarcinomas: Analysis of regional variation using the Cancer Incidence in Five Continents database (2001) Int. J. Epidemiol., 30, pp. 1415-1425Castellsagué, X., Muñoz, N., De Stefani, E., Independent and joint effects of tobacco smoking and alcohol drinking on the risk of esophageal cancer in men and women (1999) Int. J. Cancer, 82, pp. 657-664Castellsagué, X., Muñoz, N., De Stefani, E., Influence of mate drinking, hot beverages and diet on esophageal cancer risk in South America (2000) Int. J. Cancer, 8, pp. 658-664Gimeno, S.G.A., De Souza, J.M.P., Mirra, A.P., Fatores de Risco para o câncer de esôfago: Estudo caso-controle em área metropolitana da regiãp Sudeste do Brasil (1995) Ver. Saúde Pública, 29, pp. 159-165Bouchardy, C., Khlat, M., Mirra, A.P., Parkin, D.M., Cancer risks among European migrants in São Paulo Brazil (1993) Eur. J. Cancer, 29 A, pp. 1418-1423Magee, P.N., The experimental basis for the role of nitroso compounds in human cancer (1989) Cancer Surv., 8, pp. 207-239Lijinsky, W., (1992) Chemistry and Biology of N-Nitroso Compounds, , Cambridge University Press, Cambridge, UKSwann, P.F., The possible role of nitrosamines in the link between alcohol consumption and esophageal cancer in man (1984) Toxicol. Pathol., 12, pp. 357-360Yang, C.S., Smith, Y., Ishizaki, H., Hong, J.Y., Enzyme mechanisms in the metabolism of nitrosamines (1991) Relevance to Human Cancer of N-Nitroso Compounds, Tobacco Smoke and Mycotoxins, pp. 265-274. , I.K. O'Neill, J. Chen, H. Barysch (Eds.). International Agency for Research on Cancer, LyonRibeiro Pinto, L.F., Differences between isoamyl alcohol and ethanol on the metabolism and DNA ethylation of N-nitrosodiethylamine in the rat (2000) Toxicology, 151, pp. 73-79Gibel, W., Experimentelle untersuchungen zur syncarcinogenese beim oesophaguscarzinom (1967) Arch. Gerchwulstforsch, 30, pp. 181-189Ribeiro Pinto, L.F., Swann, P.F., Opium and oesophageal cancer: Effect of morphine and opium on the distribution of N-nitrosodimethylamine and N-nitrosodiethylamine in the rat (1997) Carcinogenesis, 18, pp. 365-369Ribeiro Pinto, L.F., Moraes, E., Albano, R.M., Rat oesophageal cytochrome P450 (CYP) monooxygenase system: Comparison to the liver and relevance in N-nitrosodiethylamine carcinogenesis (2001) Carcinogenesis, 22, pp. 1877-1883Patterson, C.J., Peterson, L.A., Murphy, S.E., Evidence for metabolic activation of N-nitrosonornicotine and N-nitrosomethylbenzylamine by rat nasal coumarin hydroxylase (1998) Drug Metab. Dispos., 26, pp. 177-180Chen, S.C., Wang, X., Xu, G., Depentylation of ( 3H pentyl)methyl-n-amylnitrosamine by rat oesophageal and liver microsomes and by rat and human cytochrome P450 isoforms (1999) Cancer Res., 59, pp. 91-98Godoy, W., Albano, R.M., Moraes, E.G., CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: Regional and inter-individual variation in expression and relevance to nitrosamine metabolism (2002) Carcinogenesis, 23, pp. 611-616Raunio, H., Rautio, A., Pelkonen, O., The CYP2A subfamily: function, expression, and genetic polymorphism (1999) Metabolic Polymorphisms and Susceptibility to Cancer, pp. 197-208. , P. Vineis, N. Malats, M. Lang, A. d'Errico, N. Caporaso, J. Cuzick, P. Bofetta (Eds.). International Agency for Research on Cancer, LyonLechevrel, M., Casson, A.G., Wolf, C.R., Characterization of cytochrome P450 expression in human oesophageal mucosa (1999) Carcinogenesis, 20, pp. 243-248Robottom, A.B., Aquino, S., Queiroga, R., Expression of CYP2A3 mRNA and its regulation by 3-methylcholanthrene, pyrazole, and B-ionone in different tissues of the rat (2003) Braz. J. Med. Biol. Res., 36, pp. 839-844Montesano, R., Hollstein, M., Hainaut, P., Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: A review (1996) Int. J. Cancer, 69, pp. 1-11Lam, A.K.Y., Molecular biology of esophageal squamous cell carcinoma (2000) Crit. Rev. Oncol./Hematol., 33, pp. 71-90Olivier, M., Eeles, R., Hollstein, M., The IARC TP53 database: New online mutation analysis and recommmendations to users (2002) Hum. Mutat., 19, pp. 607-614Pütz, A., Hartmann, A.A., Fontes, P.R.O., TP53 mutation pattern of esophageal squamous cell carcinoma in a high risk area (Southern Brazil): Role of life style factors (2002) Int. J. Cancer, 98, pp. 99-105Pfeifer, G.P., Hainaut, P., On the origin of G→T transversions in lung cancer (2003) Mutat. Res., 526, pp. 39-43Hayashi, S., Watanabe, J., Kawajiri, K., Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene (1991) J. Biochem., 110, pp. 559-565Wang, S., Lee, H., Chen, K., Cytochrome P4502E1 genetic polymorphisms and lung cancer in taiwanese population (1999) Lung Cancer, 26, pp. 27-34Morita, S., Yano, M., Shiozaki, H., CYP1A1, CYP2E1 and GSTM1 polymorphisms are not associated with susceptibility to squamous-cell carcinoma of the esophagus (1997) Int. J. Cancer, 71, pp. 192-195Tan, W., Song, N., Wang, G., Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high risk individuals in CHN (2000) Cancer Epidemiol. Biomarkers Prev., 9, pp. 551-556Van Lieshout, E.M.M., Roelofs, H.M.J., Dekker, S., Polymorphic expression of the glutathione S-transferase P1 gene and its susceptibility to Barretts esophagus and esophageal carcinoma (1999) Cancer Res., 59, pp. 586-589Van Lieshout, E.M.M., Van Haelst, U.J.G.M., Wobbes, T., Peters, W.H.M., Immunohistochemical localization of glutathione S-transferase A and P in human esophageal squamous epithelium, Barrett's epithelium and carcinoma (1999) Jpn. J. Cancer Res., 90, pp. 530-535Harries, L.W., Stubbins, M.J., Forman, D., Identification of gentic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer (1997) Carcinogenesis, 18, pp. 641-644Abdel-Rahman, S.Z., El-Zhein, R.A., Anwar, W.A., Au, W.W., A multiplex PCR procedure for polymorphic analysis of GSTM1 and 0 genes in population studies (1996) Cancer Lett., 107, pp. 229-233Shimoda-Matsubayashi, S., Matsumine, H., Kobayashi, T., Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene (1996) Biochem. Biophys. Res. Commun., 226, pp. 561-565Ahomadegbe, J.C., Barrois, M., Fogel, S., High incidence of TP53 alterations (mutations, deletion, overexpression) in head and neck primary tumors and metastasisAbsence of correlation with clinical outcome. Frequent protein overexpression in normal epithelium and early non-invasive lesions (1995) Oncogene, 10, pp. 874-879Lee, J.S., Alternative dideoxy sequencing of double-strand DNA by cyclic reactions using Taq polymerase (1991) DNA Cell. Biol., 10, pp. 67-7

Mutant P53 Aggregates Into Prion-like Amyloid Oligomers And Fibrils: Implications For Cancer

Over 50% of all human cancers lose p53 function. To evaluate the role of aggregation in cancer, we asked whether wild-type (WT) p53 and the hot-spot mutant R248Q could aggregate as amyloids under physiological conditions and whether the mutant could seed aggregation of the wild-type form. The central domains (p53C) of both constructs aggregated into a mixture of oligomers and fibrils. R248Q had a greater tendency to aggregate than WT p53. Full-length p53 aggregated into amyloid-like species that bound thioflavin T. The amyloid nature of the aggregates was demonstrated using x-ray diffraction, electron microscopy, FTIR, dynamic light scattering, cell viabilility assay, and anti-amyloid immunoassay. The x-ray diffraction pattern of the fibrillar aggregates was consistent with the typical conformation of cross β-sheet amyloid fibers with reflexions of 4.7 Å and 10 Å. A seed of R248Q p53C amyloid oligomers and fibrils accelerated the aggregation of WT p53C, a behavior typical of a prion. The R248Q mutant co-localized with amyloid-like species in a breast cancer sample, which further supported its prion-like effect. A tumor cell line containing mutant p53 also revealed massive aggregation of p53 in the nucleus. We conclude that aggregation of p53 into a mixture of oligomers and fibrils sequestrates the native protein into an inactive conformation that is typical of a prionoid. This prion-like behavior of oncogenic p53 mutants provides an explanation for the negative dominance effect and may serve as a potential target for cancer therapy. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.287332815228162Vousden, K.H., Lane, D.P., p53 in health and disease (2007) Nat. Rev. Mol. Cell Biol., 8, pp. 275-283Joerger, A.C., Fersht, A.R., Structural biology of the tumor suppressor p53 (2008) Annu. Rev. Biochem., 77, pp. 557-582Ishimaru, D., Andrade, L.R., Teixeira, L.S., Quesado, P.A., Maiolino, L.M., Lopez, P.M., Cordeiro, Y., Silva, J.L., Fibrillar aggregates of the tumor suppressor p53 core domain (2003) Biochemistry, 42, pp. 9022-9027Silva, J.L., Vieira, T.C., Gomes, M.P., Ano Bom, A.P., Lima, L.M., Freitas, M.S., Ishimaru, D., Foguel, D., Ligand binding and hydration in protein misfolding: Insights from studies of prion and p53 tumor suppressor proteins (2010) Acc. Chem. Res., 43, pp. 271-279Galea, C., Bowman, P., Kriwacki, R.W., Disruption of an intermonomer salt bridge in the p53 tetramerization domain results in an increased propensity to form amyloid fibrils (2005) Prot. Sci., 14, pp. 2993-3003Higashimoto, Y., Asanomi, Y., Takakusagi, S., Lewis, M.S., Uosaki, K., Durell, S.R., Anderson, C.W., Sakaguchi, K., Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer (2006) Biochemistry, 45, pp. 1608-1619Rigacci, S., Bucciantini, M., Relini, A., Pesce, A., Gliozzi, A., Berti, A., Stefani, M., The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies (2008) Biophys. J., 94, pp. 3635-3646Ishimaru, D., Ano Bom, A.P., Lima, L.M., Quesado, P.A., Oyama, M.F., De Moura Gallo, C.V., Cordeiro, Y., Silva, J.L., Cognate DNA stabilizes the tumor suppressor p53 and prevents misfolding and aggregation (2009) Biochemistry, 48, pp. 6126-6135Levy, C.B., Stumbo, A.C., Ano Bom, A.P., Portari, E.A., Cordeiro, Y., Silva, J.L., De Moura-Gallo, C.V., Co-localization of mutant p53 and amyloid-like protein aggregates in breast tumors (2011) Int. J. Biochem. Cell Biol., 43, pp. 60-64Xu, J., Reumers, J., Couceiro, J.R., De Smet, F., Gallardo, R., Rudyak, S., Cornelis, A., Schymkowitz, J., Gain of function of mutant p53 by coaggregation with multiple tumor suppressors (2011) Nat. Chem. Biol., 7, pp. 285-295Chiti, F., Dobson, C.M., Protein misfolding, functional amyloid, and human disease (2006) Annu. Rev. Biochem., 75, pp. 333-366Pastore, A., Temussi, P.A., The two faces of Janus: Functional interactions and protein aggregation (2012) Curr. Opin. Struct. Biol., 22, pp. 30-37Butler, J.S., Loh, S.N., Structure, function, and aggregation of the zinc-free form of the p53 DNA binding domain (2003) Biochemistry, 42, pp. 2396-2403Antony, H., Wiegmans, A.P., Wei, M.Q., Chernoff, Y.O., Khanna, K.K., Munn, A.L., Potential roles for prions and protein-only inheritance in cancer (2011) Cancer Metastasis Rev., 31, pp. 1-19Hollstein, M., Sidransky, D., Vogelstein, B., Harris, C.C., p53 mutations in human cancers (1991) Science, 253, pp. 49-53Olivier, M., Hollstein, M., Hainaut, P., TP53 mutations in human cancers: Origins, consequences, and clinical use (2010) Cold Spring Harb. Perspect. Biol., 2, pp. a001008Cordeiro, Y., Kraineva, J., Gomes, M.P., Lopes, M.H., Martins, V.R., Lima, L.M., Foguel, D., Silva, J.L., The amino-terminal PrP domain is crucial to modulate prion misfolding and aggregation (2005) Biophys. J., 89, pp. 2667-2676Cordeiro, Y., Kraineva, J., Ravindra, R., Lima, L.M., Gomes, M.P., Foguel, D., Winter, R., Silva, J.L., Hydration and packing effects on prion folding and β-sheet conversion. High pressure spectroscopy and pressure perturbation calorimetry studies (2004) J. Biol. Chem., 279, pp. 32354-33259Glabe, C.G., Conformation-dependent antibodies target diseases of protein misfolding (2004) Trends Biochem. Sci., 29, pp. 542-547Lai, Z., Colón, W., Kelly, J.W., The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid (1996) Biochemistry, 35, pp. 6470-6482Howie, A.J., Brewer, D.B., Howell, D., Jones, A.P., Physical basis of colors seen in Congo red-stained amyloid in polarized light (2008) Lab. Invest., 88, pp. 232-242Moll, U.M., LaQuaglia, M., Bénard, J., Riou, G., Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors (1995) Proc. Natl. Acad. Sci. U.S.A., 92, pp. 4407-4411Ostermeyer, A.G., Runko, E., Winkfield, B., Ahn, B., Moll, U.M., Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide (1996) Proc. Natl. Acad. Sci. U.S.A., 93, pp. 15190-15194Bom, A.P., Freitas, M.S., Moreira, F.S., Ferraz, D., Sanches, D., Gomes, A.M., Valente, A.P., Silva, J.L., The p53 core domain is a molten globule at low pH: Functional implications of a partially unfolded structure (2010) J. Biol. Chem., 285, pp. 2857-2866Gerweck, L.E., Tumor pH: Implications for treatment and novel drug design (1998) Semin. Radiat. Oncol., 8, pp. 176-182Gomes, M.P., Millen, T.A., Ferreira, P.S.E., Silva, N.L., Vieira, T.C., Almeida, M.S., Silva, J.L., Cordeiro, Y., Prion protein complexed to N2a cellular RNAs through its N-terminal domain forms aggregates and is toxic to murine neuroblastoma cells (2008) J. Biol. Chem., 283, pp. 19616-19625Ishimaru, D., Lima, L.M., Maia, L.F., Lopez, P.M., Ano Bom, A.P., Valente, A.P., Silva, J.L., Reversible aggregation plays a crucial role on the folding landscape of p53 core domain (2004) Biophys. J., 87, pp. 2691-2700Sunde, M., Serpell, L.C., Bartlam, M., Fraser, P.E., Pepys, M.B., Blake, C.C., Common core structure of amyloid fibrils by synchrotron X-ray diffraction (1997) J. Mol. Biol., 273, pp. 729-739Novitskaya, V., Bocharova, O.V., Bronstein, I., Baskakov, I.V., Amyloid fibrils of mammalian prion protein are highly toxic to cultured cells and primary neurons (2006) J. Biol. Chem., 281, pp. 13828-13836Vieira, M.N., Forny-Germano, L., Saraiva, L.M., Sebollela, A., Martinez, A.M., Houzel, J.C., De Felice, F.G., Ferreira, S.T., Soluble oligomers from a non-disease related protein mimic Aβ-induced tau hyperphosphorylation and neurodegeneration (2007) J. Neurochem., 103, pp. 736-748Gomes, M.P., Cordeiro, Y., Silva, J.L., The peculiar interaction between mammalian prion protein and RNA (2008) Prion, 2, pp. 64-66Elledge, R.M., Clark, G.M., Fuqua, S.A., Yu, Y.Y., Allred, D.C., p53 protein accumulation detected by five different antibodies: Relationship to prognosis and heat shock protein 70 in breast cancer (1994) Cancer Res., 54, pp. 3752-3757Moll, U.M., Valea, F., Chumas, J., Role of p53 alteration in primary peritoneal carcinoma (1997) Int. J. Gynecol. Pathol., 16, pp. 156-162Lambert, M.P., Barlow, A.K., Chromy, B.A., Edwards, C., Freed, R., Liosatos, M., Morgan, T.E., Klein, W.L., Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins (1998) Proc. Natl. Acad. Sci. U.S.A., 95, pp. 6448-6453Kayed, R., Head, E., Thompson, J.L., McIntire, T.M., Milton, S.C., Cotman, C.W., Glabe, C.G., Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis (2003) Science, 300, pp. 486-489Gottifredi, V., Prives, C., Molecular biology. Getting p53 out of the nucleus (2001) Science, 292, pp. 1851-1852Soussi, T., Béroud, C., Assessing TP53 status in human tumours to evaluate clinical outcome (2001) Nat. Rev. Cancer, 1, pp. 233-240Chowdary, D.R., Dermody, J.J., Jha, K.K., Ozer, H.L., Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway (1994) Mol. Cell Biol., 14, pp. 1997-2003Chen, L., Lu, W., Agrawal, S., Zhou, W., Zhang, R., Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2 expression (1999) Mol. Med., 5, pp. 21-34Goh, A.M., Coffill, C.R., Lane, D.P., The role of mutant p53 in human cancer (2011) J. Pathol., 223, pp. 116-126Joerger, A.C., Rajagopalan, S., Natan, E., Veprintsev, D.B., Robinson, C.V., Fersht, A.R., Structural evolution of p53, p63, and p73: Implication for heterotetramer formation (2009) Proc. Natl. Acad. Sci. U.S.A., 106, pp. 17705-17710Nicholls, C.D., McLure, K.G., Shields, M.A., Lee, P.W., Biogenesis of p53 involves cotranslational dimerization of monomers and post-translational dimerization of dimers. Implications on the dominant negative effect (2002) J. Biol. Chem., 277, pp. 12937-12945Aguzzi, A., Rajendran, L., The transcellular spread of cytosolic amyloids, prions, and prionoids (2009) Neuron, 64, pp. 783-790Frost, B., Diamond, M.I., Prion-like mechanisms in neurodegenerative diseases (2010) Nat. Rev. Neurosci., 11, pp. 155-159Park, S.J., Borin, B.N., Martinez-Yamout, M.A., Dyson, H.J., The client protein p53 adopts a molten globule-like state in the presence of Hsp90 (2011) Nat. Struct. Mol. Biol., 18, pp. 537-541Kocisko, D.A., Vaillant, A., Lee, K.S., Arnold, K.M., Bertholet, N., Race, R.E., Olsen, E.A., Caughey, B., Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides (2006) Antimicrob. Agents Chemother., 50, pp. 1034-1044Caughey, B., Caughey, W.S., Kocisko, D.A., Lee, K.S., Silveira, J.R., Morrey, J.D., Prions and transmissible spongiform encephalopathy (TSE) chemotherapeutics: A common mechanism for anti-TSE compounds? (2006) Acc. Chem. Res., 39, pp. 646-653Vieira, T.C., Reynaldo, D.P., Gomes, M.P., Almeida, M.S., Cordeiro, Y., Silva, J.L., Heparin binding by murine recombinant prion protein leads to transient aggregation and formation of RNA-resistant species (2010) J. Am. Chem. Soc., 133, pp. 334-34

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). Interpretation Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron