Molecular Targeting

Neuro-endocrine tumors: cellular and molecular mechanisms

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.

 

Project of physiopathological impact and molecular mechanisms of inflammatory mediators

Investigating the mechanisms controlling GR associated co-chaperones activity represents an important issue to understand the molecular underpinnings contributing to HPA function and related disorders.

Dynamic regulation of the molecular properties of these proteins by SUMOylation, contributes to further understanding the complexity of GR and co-chaperone-mediated processes in health and disease. In this context we have recently described that antidepressants inhibit PIAS4-mediated SUMOylation of FKBP51, an important inhibitor of the glucocorticoid receptor (GR) signaling. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity. The work describes that tricyclic antidepressants inhibit FKBP51 SUMOylation, and that this inhibition caused by the decreased interaction of FKBP51 with PIAS4, directly impacts on the negative regulatory functions of FKBP51 on GR (which is deregulated in stress-related diseases). Thus, the action of antidepressants as repressors of FKBP51 SUMOylation acts as a molecular switch that helps to restore glucocorticoid receptor sensitivity. These findings provide new potential routes of antidepressant intervention, which we continue to explore.

Our group continues several collaborations on the molecular mechanisms of GR action and inflammatory mediators.