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Study of the control of gene expression lncRNA INXS involved in the apoptosis

Grant number: 15/00324-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2015
Effective date (End): August 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Sergio Verjovski Almeida
Grantee:Alexandre Videira
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/03620-2 - Characterization of the mechanisms of action of long non-coding RNAs involved with gene activation programs in human cells, AP.TEM

Abstract

The discovery of countless long non-coding RNA (lncRNAs, > 200 nucleotides) transcripts in the human genome dramatically altered our understanding of cell biology, especially the mechanisms involved in the process of programmed cell death. Apoptosis is a plenty regulated process that plays an essential role in the development and tissue homeostasis. The dysregulation of natural defense mechanism promote aberrant cell proliferation and accumulation of genetic mutations, resulting in tumorigenesis, and often confers resistance to drugs for cancer cells. A complex network of signaling pathway acts to promote or inhibit apoptosis in response to various intra- and extracellular stimuli, and between the flags are alternative splicing of the transcript BCL-X (BCL-2 family member) which gives the product anti-apoptotic BCL-XL, and pro-apoptotic BCL-XS. Our studies found that the lncRNA INXS is mediator of the splicing, leading to the formation of BCL-XS and causing apoptosis, and showed that INXS had reduced expression in various types of tumors, which is consistent with the fact that tumor cells are more resistant to cell death. Lack determine the factors that cause this reduction in INXS expression in tumors. For this, in this project we will featuers the minimal promoter INXS using reporter assay and we will featuers transcription factors that bind the promoter region of INXS between different cell types using pull-down proteins that bind to INXS followed by western -blot and / or mass spectrometry. Functional characterization of the promoter will provide an understanding of the mechanisms that lead to transcription lncRNA INXS. In addition, we will evaluate the specific allele expression using smFISH, which provide an understanding of the coordinated expression of INXS and BCL-X, involving the promoter and changes in chromatin. This study will advance the possible exploitation of lncRNA INXS as a target in cancer therapy. (AU)

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