GENE EXPRESSION REGULATION increases the functional versatility and adaptability of the cell by allowing it to express certain proteins when needed. It is, therefore, one of the most important and complex processes of biology. Changes in the gene expression patterns are key in cancer cell transformation, through an increase in expression of genes that promote carcinogenesis (oncogenes) and/or a decrease in expression of genes that prevent it (tumour suppressor genes). MicroRNAs (miRNAs) and chromatin-structure both play important roles in this process and have been found to be critical in the development of human pathologies. Both of these regulatory elements, especially in the context of CANCER, have been the focus of my interest during my career.
Implicaciones de los complejos remodeladores de cromatina en el desarrollo tumoral. The SWI/SNF complex is an ATP-dependent chromatin-remodelling complex that is known to regulate EPIGENETICALLY the gene expression (Kwon, Imbalzano et al. 1994). Increasing evidence demonstrates that some components of the SWI/SNF complex are tumour suppressors and are involved in human cancer development. One subunit of this complex, SNF5, is inactivated in malignant rhabdoid tumours (MRTs) and heterozygous Snf5 knockout mice develop tumours that are histologically similar to human MRTs (Roberts, Galusha et al. 2000; Roberts, Leroux et al. 2002). BRG1 (Medina and Sanchez-Cespedes 2008), the helicase/ATPase catalytic subunits of the SWI/SNF complex, is mutated in many different cancer cell lines (Wong, Shanahan et al. 2000; Medina, Romero et al. 2008). Additionally, germline BRG1 mutations linked to a Rhabdoid Tumour Predisposition Syndrome was reported in a family, strongly suggesting that is a bona fide tumour suppressor gene (Schneppenheim, Fruhwald et al.). Recently, it has been discovered that two other subunits of the chromatin-remodelling complex, BAF250 (ARID1A) and BAF180 (PBRM1) (Jones, Wang et al. ; Wiegand, Shah et al. ; Varela, Tarpey et al. 2011; Wilson and Roberts 2011), are frequently mutated in ovarian clear cell carcinoma and renal carcinoma, respectively. All these observations support an important role of the SWI/SNF complex in cancer, however its specific function is still unclear.
Implicaciones de los ARN no codificantes de proteínas en el desarrollo tumoral.MiRNAs are a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. Due to their small size and unusual nature, miRNAs were not discovered in humans until 2000. Today, over one thousand miRNAs have been identified in the human genome. Aberrant biogenesis and/or expression of miRNAs have been linked to human diseases including cancer (Medina and Slack 2008). During my training as a postdoc in this field I have helped to reveal the critical role played by specific miRNAs in cancer. While most previous studies in the field used cell lines or in vitro systems, we pioneered the functional study of the role of miRNAs using in vivo transgenic mouse models. We demonstrated the therapeutic utility of let-7 microARN ectopic expression in vivo (Medina, Trang et al. 2010), and the important of a single microARNs (miR-21) to the drive of tumor development (Medina, Nolde et al. 2010). In my recently created group at the GenyO Center we will continue unveiling the role of the microRNAs in cancer with the hope to find novel and useful cancer therapies.
7º Programa Marco de la Comunidad Europea.
Programa Nacional de Proyectos de Investigación Fundamental no Orientada.
Junta de Andalucía
Consejería de Salud de la Junta de Andalucía
Campus of International Excellence of BioHealth, Information Communications and Technology.
Carlos Baliñas-Gavira, María I. Rodríguez, Alvaro Andrades, Marta Cuadros, Juan Carlos Álvarez-Pérez, Ángel F. Álvarez-Prado, Virginia G. de Yébenes, Sabina Sánchez-Hernández, Elvira Fernández-Vigo, Javier Muñoz, Francisco Martín, Almudena R. Ramiro, José A. Martínez-Climent & Pedro P. Medina 06/2020 – Leukemia.
Coira IF, Rufino-Palomares EE, Romero OA, Paola Peinado, Chanatip Metheetrairut, Boyero-Corral L, Carretero J, Farez-Vidal E, Cuadros M., Reyes-Zurita F, Lupiáñez JA, Sánchez-Cespedes M., Slack FJ, Medina PP. 03/2015 – Human Molecular Genetics. Article awarded by the Royal Academy of Medicine of Salamanca
Medina P.P., Mona Nolde and Frank J. Slack 09/2010 – Nature. Must read article, according to Faculty of 1000
Ranked among the top 1% of the publications more cited in clinical medicine according to Essential Science Indicators (Thomson Reuters).