Chaperone proteins in cardioprotection
Prof.ssa Mara Brancaccio (Principal Investigator)
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Activities The rhythmic heart beating is ensured by the efficiency of sarcomere structures, impressive molecular machineries consisting of hundreds of proteins held together by non covalent bonds. Chaperone proteins are in charge of sarcomere protein quality control and turnover to maintain efficiency and to allow physiological adaptation to new physiological conditions.Melusin is a chaperone protein, selectively expressed in skeletal and cardiac muscles. It functions as a mechanical stretch sensor in muscle cells thanks to its ability to bind the cytoplasmic region of beta 1 integrin and to activate MAPK and PI3K/AKT intracellular signaling, leading to cardiomyocyte hypertrophy and survival. Melusin overexpression in cardiomyocytes improves myocardial function in different stress conditions, like pressure overload, myocardial infarction and ischemia/reperfusion injury. We are interested in clarifying the molecular mechanisms by which melusin exerts its impressive protective function and in evaluating the potential of melusin-based gene therapy approaches to cure cardiomyopathy.(https://brancacciolab.com/) |
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Vitadello M, Sorge M, Percivalle E, Germinario E, Danieli-Betto D, Turco E, Tarone G, Brancaccio M, Gorza L. Loss of melusin is a novel, neuronal NO synthase/FoxO3-independent master switch of unloading-induced muscle atrophy. J Cachexia Sarcopenia Muscle. 2020 Mar 10. doi: 10.1002/jcsm.12546. [Epub ahead of print] PMID: 32154658 Penna C, Sorge M, Femminò S, Pagliaro P, Brancaccio M. Redox Aspects of Chaperones in Cardiac Function. Front Physiol. 2018 Mar 16;9:216. doi: 10.3389/fphys.2018.00216. PubMed PMID: 29615920. Sorge M, Brancaccio M. Melusin Promotes a Protective Signal Transduction Cascade in Stressed Hearts. Front Mol Biosci. 2016 Sep 12;3:53. doi:10.3389/fmolb.2016.00053. Tarone G, Brancaccio M. The muscle-specific chaperone protein melusin is a potent cardioprotective agent. Basic Res Cardiol. 2015 Mar;110(2):466. doi: 10.1007/s00395-015-0466-9. Epub 2015 Feb 5. Penna C*, Brancaccio M*, Tullio F, Rubinetto C, Perrelli MG, Angotti C, Pagliaro P, Tarone G. Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury. Basic Res Cardiol. 2014 Jul;109(4):418. doi: 10.1007/s00395-014-0418-9. Epub 2014 May 25. Tarone G, Brancaccio M. Keep your heart in shape: molecular chaperone networks for treating heart disease. Cardiovasc Res. 2014 Jun 1;102(3):346-61. doi: 10.1093/cvr/cvu049. Tarone G, Sbroggiò M, Brancaccio M. Key role of ERK1/2 molecular scaffolds in heart pathology. Cell Mol Life Sci. 2013 Nov;70(21):4047-54. doi: 10.1007/s00018-013-1321-5. Epub 2013 Mar 27. Ferretti R, Sbroggiò M, Di Savino A, Fusella F, Bertero A, Michowski W, Tarone G, Brancaccio M. Morgana and Melusin: Two fairies chaperoning signal transduction. Cell Cycle. 2011 Nov 1;10(21):3678-83. doi: 10.4161/cc.10.21.18202. Epub 2011 Nov 1. Sbroggiò M, Bertero A, Velasco S, Fusella F, De Blasio E, Bahou WF, Silengo L, Turco E, Brancaccio M*, Tarone G*. ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci. 2011, 124:3515-24. Mauro Sbroggiò, Roberta Ferretti, Elena Percivalle, Malgorzata Gutkowska, Alicja Zylicz, Wojciech Michowski, Jacek Kuznicki, Federica Accornero, Beniamina Pacchioni, Gerolamo Lanfranchi, Jorg Hamm, Emilia Turco, Lorenzo Silengo, Guido Tarone and Mara Brancaccio. The mammalian CHORD-containing protein melusin is a stress response protein interacting with Hsp90 and Sgt1. (2008) FEBS Lett. 582:1788-1794 Mara Brancaccio, Emilio Hirsch, Antonella Notte, Giulio Selvetella, Giuseppe Lembo, Guido Tarone. Integrin signalling: The tug-of-war in heart hypertrophy. (2006) Cardiovasc Res.,70:422-33 Mara Brancaccio, Nadia Menini, Daniela Bongioanni, Roberta Ferretti, Marika De Acetis, Lorenzo Silengo, Guido Tarone. Chp-1 and melusin, two CHORD containing proteins in vertebrates (2003). FEBS Lett., 551: 47-52. Mara Brancaccio, Luigi Fratta, Antonella Notte, Emilio Hirsch, Roberta Poulet, Simona Guazzone, Marika De Acetis, Carmine Vecchione, Gennaro Marino, Fiorella Altruda, Lorenzo Silengo, Guido Tarone & Giuseppe Lembo. Melusin, a muscle-specific integrin β1–interacting protein, is required to prevent cardiac failure in response to chronic pressure overload (2003). Nat Med; 9:68-75 Mara Brancaccio, Simona Guazzone, Nadia Menini, Elena Sibona, Emilio Hirsch, Marco De Andrea, Mariano Rocchi, Fiorella Altruda, Guido Tarone, Lorenzo Silengo. Melusin is a new muscle-specific interactor for b1 integrin cytoplasmic domain. (1999) J. Biol. Chem 274:29282-29288
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We are deeply interested in two different lines of research. On the one hand, we are investigating the role of morgana in tumor onset and progression, by dissecting the molecular mechanisms involved in morgana action. On the other hand, we are involved in understanding the molecular basis of maladaptive versus compensatory remodeling in the heart subjected to stress, where melusin may represent an important protective agent.
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