Research lines

The main defining characteristic of tumor processes is the alteration of cellular homeostasis. The mechanisms that can cause such alteration include cell cycle deregulation, abnormal intracellular signaling,and defects in the processes of protein posttranslational modification. The detailed characterization of these mechanisms and how they contribute to malignant transformation are the main objectives of our research group. Elucidation of these mechanisms may helpin the search for new therapeutic strategies to be implemented in clinical practice.

We study the molecular mechanisms involved in the control of cell homeostasis through 3 general areas of interest that define the 3 main research lines on which our group is structured:

RESEARCH LINE 1.The Retinoblastoma/E2F pathway in cell cycle regulation

The Rb/E2F pathway plays a critical role in the regulation of DNA replication and cell cycle progression. In fact, the transcriptional activity of E2F factors is deregulated in virtually all cancers. Up to 8 E2F family member genes have been identified. The specific and shared functions of each E2F memberare still unclear. The goal of this line is to investigate these functions.

On one hand, we are studying the molecular mechanism by which E2F1 and E2F2 regulate pancreatic pathophysiology. Using genetically modified mice, we are analyzing the mechanisms involved in the diabetes and pancreatic degeneration shown by knockout mice for E2F1/2. At the same time, we are carrying out the functional characterization of a group of E2F2-interacting proteins recently identified by our group using proteomic approaches.

On the other hand, we are examining the regulation and function of E2F7. Using RNA-Seq, ChIP- Seq, and Proteomics methodologies, we are identifying and functionally characterizing E2F7 target genes (mRNAs and microRNAs). We are also investigatingthe proteins that interact with this E2F factor, in an attempt to understand how its deregulated activity may contribute to genomic instability.

RESEARCH LINE 2. Monomeric GTPases and their role in intracellular signaling

The coordination of intracellular signals is key for the cells to respond in a controlled manner to the messages they receive. Our research focuses in understanding how cells integrate the signals that regulate cellular metabolism with the different signaling networks that lead to gene activation and cell cycle entry, and its control by protein ubiquitylation. Specifically, we are studying how the signal emanating from the IL-2 receptor is processed to activate the RacGTPase and Glycogen Phosphorylase(PYG). We also investigate how the Rac1/ PYGsignaling pathway exerts its regulation at a genomic level on cell cycle and cell proliferation.

RESEARCH LINE 3.Ubiquitylation and nucleocytoplasmic transport of proteins in tumor development

In this research we study two interrelated processes that are critical to the proper functioning of many cellular proteins: ubiquitylation and transport between the nucleus and cytoplasm. We study how alterations of these processes contribute to the development of tumors, with the ultimate goal of designing and facilitating the implementation of new therapeutic strategies in cancer. We focus, on one hand, in a family of ubiquitylation-regulatory enzymes termeddeubiquitinases (DUBs) and, on the other hand, in the main nuclear export receptor, CRM1.

Regarding the DUBs, we use proteomics, site-directed mutagenesis and gene silencing to identify new substrates of two of these enzymes, USP1 and USP21. We aim to understand how the altered activity of these DUBs may contribute to cellular transformation. In addition, we use in vitro assays to evaluate the therapeutic potential of new USP1 inhibitors.

As for CRM1, we are conducting a systematic study of its interactome (the set of cellular proteins that interact with this receptor), and a functional analysis of the CRM1 mutant variants identified in patients with chronic myeloid leukemia (CML). CRM1 inhibitors represent a new class of antitumor agents that are currently being evaluated in clinical trials. With our basic studies on this protein we can contribute to the development of these new inhibitors, by identifying biomarkers to help predict potential adverse effects and the response of different patients to treatment.