La hipófisis manifiesta una gran plasticidad morfológica y funcional en respuesta a múltiples señales a fin de mantener la homeostasis glandular. No obstante, es muy frecuente la aparición de tumores hipofisarios los cuales representan el 15% de los tumores intracraneales. La mayor parte de estos tumores permanecen con un tamaño estable y clínicamente ocultos y recientes avances han asociado los mecanismos de senescencia celular prematura con las características benignas de estos adenomas. La senescencia celular, interpretada como una alternativa en la respuesta al estrés celular, está caracterizada por un arresto del ciclo que puede ser desencadenado por factores intrínsecos y extrínsecos de estrés. Recientemente, hemos demostrado claras evidencias del surgimiento de la senescencia hipofisaria durante el desarrollo de tumores hipofisarios experimentales murinos inducidos por estrógenos in vivo. La presente línea de investigación está focalizada en el estudio de mecanismos fisiológicos genuinos que se desencadenan con la finalidad de proteger la transformación tumoral hipofisaria humana: senescencia celular, propuesta como barrera de vigilancia tumoral. Dado que este mecanismo constituye una importante barrera de protección tumoral, analizar los mecanismos moleculares que subyacen a la capacidad de las células hipofisarias para escapar del crecimiento invasivo y transformación maligna proporcionaría importantes conocimientos sobre nuevas vías de evasión tumoral.
-Integrantes del Grupo de Trabajo:
Director:
Ana Lucía DE PAUL. Investigadora Independiente. Profesora Adjunta
Becarios:
Ezequiel GRONDONA, Becario Posdoctoral CONICET
Dr. Favio PESAOLA, Becario Posdoctoral CONICET
Biol. Ana Clara VENIER, Becaria DOCTORAL, FONCYT, ANPCyT
Med. Silvia FERNANDEZ, Tesista de doctorado.
Estudiante Clara BERTETTI, Tesinista de Grado, FCM-UNC
Publicaciones desde 2012-2021:
– 17β-estradiol stimulates the translocation of endogenous estrogen receptor α at the plasma membrane of normal anterior pituitary cells. Gutiérrez S, Sosa L, Petiti JP, Mukdsi JH, Mascanfroni I, Pellizas C, De Paul AL, Cambiasso MJ, AI Torres. Mol Cell Endocrinol. 355: 169-179, 2012.
– Cooperative effect of E2 and FGF2 on lactotroph proliferation triggered by signalling initiated at the plasma membrane. Ldel V. Sosa, S Gutiérrez, JP. Petiti, Vaca, AM, AL. De Paul, AI Torres. Am J Physiol Endocrinol Metab. 305: E41-9. 2013.
– Functional Toll-like receptor 4 expressed in lactotrophs mediates LPS-induced proliferation in experimental pituitary hyperplasia. ME Sabatino, LSosa, J Petiti, J Mukdsi, I Mascanfroni, C G Pellizas, S Gutiérrez, AI Torres and Ana L De Paul. Exp Cell Res. 319:3020-34. 2013.
– Testosterone abrogates TLR4 activation in prostate smooth muscle cells contributing to the preservation of a differentiated phenotype. Leimgruber C, Quintar AA, García LN, Petiti JP, De Paul AL, Maldonado CA. J Cell Physiol 228(7):1551-60. 2013.
– Diphenyl diselenide administration enhances cortical mitochondrial number and activity by increasing hemeoxygenase type 1content in a methylmercury-induced neurotoxicity mouse model. V Glaser, RDP Martins, AJ Hoffmann Vieira, EDM Oliveira, MR Straliotto, J Mukdsi, AI Torres, A Fabro de Bem, M Farina, JB Teixeira da Rocha, A De Paul, A Latini. Mol Cell Biochem, 390:1-8. 2014.
– Glutamate Release Machinery is Altered in the Frontal Cortex of Rats with Experimental Autoimmune Encephalomyelitis. N. Chanaday, A. Vilcaes, A. De Paul, AI. Torres, A. Degano and G. Roth. Mol. Neurobiol. 51:1353-67; 2015.
– Involvement of MEK/ERK1/2 and PI3K/Akt pathways in the refractory behavior of GH3B6 pituitary tumor cells to the inhibitory effect of TGFβ1. Petiti, JP, Sosa, LdV, Sabatino, ME, Vaca, AM, Gutiérrez, S, De Paul, AL, and Torres, AI. Endocrinology. 156: 534-47, 2015.
– Evidence of cellular senescence during the development of estrogen-induced pituitary tumors. Sabatino ME, Petiti JP, Sosa LD, Pérez PA, Gutiérrez S, Leimgruber C, Latini A, Torres AI, De Paul AL. Endocr Relat Cancer. 22:299-317. 2015.
– Inhibitory role of ERβ on anterior pituitary cell proliferation by controlling the expression of proteins related to cell cycle progression. Pérez PA, Petiti JP, Wagner IA, Sabatino ME, Sasso CV, De Paul AL, Torres AI, Gutiérrez S. Mol Cell Endocrinol.; 415:100-13. 2015.
– Riboflavin acetate induces apoptosis in squamous carcinoma cells after photodynamic therapy. Juarez AV, Sosa LdV, De Paul AL, Costa AP, Farina M, Leal RB, Torres AI, Pons P. J. Photochem Photobiol B. 153:445-454. 2015.
– Uric acid activates NRLP3 inflammasome in an in-vivo model of epithelial to mesenchymal transition in the kidney. Romero C, Remor A, Latini A, Paul AL, Torres AI, Mukdsi J. J Mol Histol. 48 :209-218. 2017.
– Estrogen receptor β regulates the tumoral suppressor PTEN to modulate pituitary cell growth. Perez PA, Petiti JP, Picech F, Guido CB, dV Sosa L, Grondona E, Mukdsi JH, De Paul AL, Torres AI, Gutierrez S. J Cell Physiol. 233:1402-1413. 2018.
– Trastuzumab inhibits pituitary tumor cell growth modulating the TGFB/SMAD2/3 pathway. Petiti JP, Sosa LDV, Picech F, Moyano Crespo GD, Arevalo Rojas JZ, Pérez PA, Guido CB, Leimgruber C, Sabatino ME, García P, Bengio V, Papalini FR, Estario P, Berhard C, Villarreal M, Gutiérrez S, De Paul AL, Mukdsi JH, Torres AI. Endocr Relat Cancer. 25(10):837-852. 2018.
– Oxidative stress and mitochondrial adaptive shift during pituitary tumoral growth. Sabatino ME, Grondona E, Sosa LDV, Mongi Bragato B, Carreño L, Juarez V, da Silva RA, Remor A, de Bortoli L, de Paula Martins R, Pérez PA, Petiti JP, Gutiérrez S, Torres AI, Latini A, De Paul AL. Free Radic Biol Med 20;120:41-55. 2018.
– Anti-glioma properties of DVL, a lectin purified from Dioclea violacea. Nascimento APM, Knaut JL, Rieger DK, Wolin IAV, Heinrich IA, Mann J, Juarez AV, Sosa LDV, De Paul AL, Moreira CG, Silva IB, Nobre CS, Osterne VJS, Nascimento KS, Cavada BS, Leal RB. Int J Biol Macromol 120(Pt A):566-577. 2018.
– The ERα membrane pool modulates the proliferation of pituitary tumours. Sosa LDV, Petiti JP, Picech F, Chumpen S, Nicola JP, Perez P, De Paul A, Valdez-Taubas J, Gutierrez S, Torres AI. J Endocrinol. 240(2):229-241. 2019.
-De novo tetrahydrobiopterin biosynthesis is impaired in the inflammed striatum of parkin(-/-) mice. de Paula Martins R, Glaser V, Aguiar AS Jr, de Paula Ferreira PM, Ghisoni K, da Luz Scheffer D, Lanfumey L, Raisman-Vozari R, Corti O, De Paul AL, da Silva RA, Latini A. Cell Biol Int 42(6):725-733. 2018.
-Sosa LDV, Petiti JP, Picech F, Chumpen S, Nicola JP, Pérez PA, De Paul AL, Valdez Taubas J, Gutiérrez S, Torres AI. The ERα membrane pool modulates the proliferation of pituitary tumours. J Endocrinol. 2019 Feb 1;240(2):229-241. doi: 10.1530/JOE-18-0418.
– Remor Aline Pertile, da Silva Rodrigo Augusto, de Matos Filipe José, Glaser Viviane, de Paula Martins Roberta, Ghisoni Karina, Scheffer Débora da Luz, Carleto Andia Denise, Portinho Daniele, de Souza Ana Paula, de Oliveira Paulo Alexandre Prediger, Rui Daniel, Torres Alicia I., Mueller Linhares Rose Marie, Walz Roger, Ronsoni Marcelo Fernando, Hohl Alexandre, Rafacho Alex, Aguiar Jr. Aderbal Silva, De Paul Ana Lucia, Latini Alexandra. Chronic metabolic derangement-induced cognitive deficits and neurotoxicity are associated with REST inactivation. Mol Neurobiol. 2019 Mar;56(3):1539-1557. doi: 10.1007/s12035-018-1175-9.
-Mongi-Bragato Bethania; Grondona Ezequiel; Sosa Liliana del Valle; Zlocowski Natacha; Venier Ana Clara; Torres Alicia; Latini Alexandra; Leal Rodrigo Bainy; Gutiérrez Silvina; De Paul Ana Lucía. Pivotal role of NF-kB in cellular senescence of experimental pituitary tumours. Journal of Endocrinology, 2020. 245:2 179–191. doi.org/10.1530/JOE-19-0506.
– Pérez Pablo A; Toledo Jonathan; Sosa Liliana V; Peinetti Nahuel; Torres Alicia I; De Paul Ana L; Gutiérrez Silvina. The phthalate DEHP modulates the estrogen receptors α and β increasing lactotroph cell population in female pituitary glands. Chemosphere. Chemosphere. 2020 Nov; 258:127304. doi: 10.1016/j.chemosphere.2020.127304.
-Bravo-Miana RDC, Della Vedova AB, De Paul AL, Remedi MM, Guantay ML, Gilardoni MB, Pellizas CG, Donadio AC. Thyroid tumor cells-fibroblasts crosstalk: Role of extracellular vesicles. Endocrine Connections 9(6): 503-518. 2020. DOI: 10.1530/EC-20-0113.
-Matilde Inés Rendón, Laura Anahí Cecenarro, Marta C. Andrada, Mariela Susana Barovero, María Lorena Bertolino, Mariela Cagliolo, Ágata R. Carpentieri , Roxana Analía Damilano, Juan Carlos De Battista, Paula Estario, Silvia Fernández, Maria Eugenia Márquez , Natalia Monteserin, María Lorena Quintero, Claudia Susana Sala, Gabriela Alejandra Sosa, María Elena Surraco, Ana Lucía De Paul, Paula Szafryk de Mereshian, Carolina Fux Otta. Surgical treatment in acromegaly: experience in Córdoba. Rev Fac Cien Med Univ Nac Cordoba. 2020 Dec 9;77(4):301-306. doi: 10.31053/1853.0605.v77.n4.29073
-Wolin IAV, Heinrich IA, Nascimento APM, Welter PG, Sosa LDV, De Paul AL, Zanotto-Filho A, Nedel CB, Lima LD, Osterne VJS, Pinto-Junior VR, Nascimento KS, Cavada BS, Leal RB. ConBr lectin modulates MAPKs and Akt pathways and triggers autophagic glioma cell death by a mechanism dependent upon caspase-8 activation. Biochimie. 2021 7;180:186-204. doi: 10.1016/j.biochi.2020.11.003.
– Pesaola Favio; Quassollo Gonzalo; Venier Ana Clara; De Paul, Ana Lucía; Noher Inés; Bisbal Mariano. The neuronal ceroid lipofuscinosis-related protein CLN8 regulates endo-lysosomal dynamics and dendritic morphology. Biol Cell. 2021 May 22. doi: 10.1111/boc.202000016. Online ahead of print.
-Favio Pesaola, Guillermo Guelbert, Ana Clara Venier, Inés Adriana Cismondi, Adriana Becerra, Juan Carlos G. Vazquez, Elmer Fernandez, Ana Lucia De Paul, Norberto Guelbert and Inés Noher. Atypical Phenotypes of Neuronal Ceroid Lipofuscinosis: The Argentine Experience in the Genomic Era. Journal of Inborn Errors of Metabolism & Screening 2021, Volume 9: e20210009 DOI: https://doi.org/10.1590/2326-4594-JIEMS-2021-0009.