Effects of translation regulation via RSKs in Glioblastomas

• Grant number: 16/03858-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2016
• End date: May 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Martín Roffé
• Grantee: Danielle Pereira Nascimento
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

The RSKs (RSK1-4) are a family of kinases constituted by four human isoforms (RSK 1- 4) directly regulated by the Ras-ERK1/2 pathway. The RSKs regulate several cellular functions, such as proliferation and the control of transcription and translation. The deregulation of RSKs seems to be responsible for different oncogenic outcomes in several types of tumors. Nevertheless, the function of RSKs in glioblastoma (GBM) was not described so far. GBM is the most frequent malignant brain tumor and shows high levels of mortality given its aggressiveness and low response to the available treatments, which implicates in an overall patient survival lower than two years. Thus, it is essential to describe the altered signaling pathways and the functions that are regulated in GBMs in order to understand the molecular behavior of this type of tumor, possibly leading to the development of more effective therapies. Therefore, we aim to study the processes involved in tumorigenesis that are regulated via RSKs. The presented project will focus on the evaluation of the role of RSKs in the control of mRNAs translation in GBMs and the signaling pathways modulated by RSKs activation that might be altered in GBMs. This project involves the use of knockout cells for RSKs generated through the CRISPR-Cas9 system. Considering that the main mediator of RSKs-dependent translation is mTORC1, this pathway and its effects on translation levels will also be studied. Besides, we intend to identify mRNAs that are translated in a RSK-dependent manner using a translatomics approach. With that, we will contribute to build a solid basis for the development of new strategic therapies directed to GBMs.