María Belén Elguero, Mariana Fuertes.
David Gonilski Pacin, Florencia L. Herbstein, Josefina Rosmino.
Carolina Cárdenas (Master’s Student), Nicolás Esteban Ciancio del Giudice.
RSUME action on the adaptive response to hypoxia and tumorigenic process
Hypoxic stress activates diverse signal transduction pathways including posttranslational modification with SUMO. The aim of this project is to understand the molecular mechanisms used by RSUME, a protein identified in our laboratory as an enhancer of the SUMOylation pathway in the adaptive response to hypoxia. Specifically, our group studies how the activity of VHL and of hypoxia-inducible factors (HIFs) are modulated by RSUME, especially in the context of the processes of angiogenesis and vascularization. Our aim is to characterize the role of RSUME in tumorigenesis, and to contribute to the understanding of the molecular mechanisms involved in the development of Von Hippel Lindau (VHL) tumors, such as pheocromocytomas and Renal Cell Carcinomas (RCC).
Pituitary adenomas are benign monoclonal neoplasms that arise from the different cell types that compose the anterior pituitary. It is known that genetic/epigenetic events, hormonal stimulation and growth factors are involved in the beginning and the development of pituitary adenomas. The main goal of our research is to characterize this interaction, at the molecular and functional levels, in order to find etiological agents and molecules involved in tumor development and progression that might serve as a basis for future therapeutic strategies.
In addition to the study of RSUME in pituitary tumors processes, we approach this goal by conducting the following research topics:
Role of IL-6 in the senescence of pituitary tumors
We have described that the autocrine signal of interleukin 6 (IL-6) induces in pituitary adenomas, senescence, a mechanism that consists in the irreversible arrest of the cell cycle as a protective response to neoplastic transformation. We focus on the mechanisms of this pathway of IL-6 in the senescence of pituitary adenomas, considering it could contribute to the benign nature of these tumors.
Role of BMP-4 in pituitary tumors
Our group described that Bone Morphogenic Protein 4 (BMP-4) plays a dual role in pituitary tumor pathogenesis, promoting the proliferation of prolactinomas and inhibiting corticotropic tumorigenesis, in which retinoic acid (RA) acts as upstream effector of the inhibitory effect of BMP-4. We study the mechanisms by which RA exerts its action on BMP-4, in order to identify specific factors to understand the differential action of BMP-4 in pituitary tumorigenesis.
Publications related to this project
- Tedesco L, Elguero B, Pacin DG, Senin S, Pollak C, Garcia Marchiñena PA, Jurado AM, Isola M, Labanca MJ, Palazzo M, Yankilevich P, Fuertes M, Arzt E.
Von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME.
Cell Death Dis. 10:266 (2019).
- Fuertes M., Sapochnik M., Tedesco L., Senin S., Attorresi A., Ajler P., Carrizo G., Cervio A., Sevlever G., Bonﬁglio JJ., Stalla GK., Arzt E.
Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity.
Endocr Relat Cancer 25:665-676 (2018)
- Sapochnik M, Haedo MR, Fuertes M, Ajler P, Carrizo G, Cervio A, Sevlever G, Stalla GK, Arzt E.
Autocrine IL-6 mediates pituitary tumor senescence.
Oncotarget 8:4690-4702 (2017)
- Gerez J, Tedesco L, Bonfiglio JJ, Fuertes M, Barontini M, Silberstein S, Wu Y, Renner U, Páez-Pereda M, Holsboer F, Stalla GK, Arzt E
RSUME inhibits VHL and regulates its tumor suppressor function.
Oncogene 34: 4855-4866 (2015)
- Antico Arciuch VG, Tedesco L, Fuertes M, Arzt E
Role of RSUME in inflammation and cancer.
FEBS Lett. 589:3330-5 (2015)
- Perez Castro, C.; Renner, U.; Haedo, M.; Gunter, K.; Stalla, G.K.; Arzt, E.
Cellular and Molecular Specificity of Pituitary Gland Physiology.
Physiological Reviews 92:1-38 (2012)
- Giacomini D, Páez-Pereda M, Stalla J, Stalla GK, Arzt E.
Molecular interaction of BMP-4, TGF-beta, and estrogens in lactotrophs: impact on the PRL promoter.
Mol Endocrinol. 23:1102-1114 (2009)
- Arzt E, Chesnokova V, Stalla GK, Melmed S.
Pituitary adenoma growth: a model for cellular senescence and cytokine action.
Cell Cycle 8:677-678 (2009)
- Carbia-Nagashima, A., Gerez, J., Perez-Castro, C., Paez-Pereda, M., Silberstein, S., Stalla, G.K., Holsboer, F., Arzt, E.
A new small RWD-containing protein enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia.
Cell 131:309-323 (2007)
- Castillo, V., Giacomini, D., Páez- Pereda M., Stalla, J., Labeur, M., Theodoropoulou, M., Holsboer, F., Grossman, A.B., Stalla, G.K., Arzt, E.
Retinoic acid as a novel medical therapy for Cushing’s disease in dogs.
Endocrinology 147:4438-4444 (2006)