Identification of the Epithelial Splicing Regulatory Proteins (ESRPs) in a firefly luciferase-based high throughput cDNA expression screen. Tissue culture plates containing cDNAs placed separately in individual wells were used to screen cells containing the splicing reporter (top). cDNAs that entered the cells and caused the reporter to switch splicing produced firefly luciferase (Luc). One of the wells that "glowed" contained a cDNA for one of the ESRPs, leading to its identification. A blow up of this well is shown at the bottom with a schematic presentation of a cell containing the reporter. A cDNA for ESRP (boxed) entered the cell nucleus (light blue) and was transcribed into ESRP protein (oval). When ESRP enhanced the splicing of an exon (red), the resulting mRNA produced luciferase protein in the cytoplasm of the cell. (Credit: Russ P. Carstens, MD, University of Pennsylvania School of Medicine)
A recent discovery by the researchers at the University Of Pennsylvania School Of Medicine showing a master switch that could disable cancer cells from metastasizing from primary tumour to other organs in the body. This master switch itself is a type of protein with the function of maintaining the normal cellular function of epithelial cells.
When it is "switched off", epithelial cells gain the characteristic of mesenchymal cells which have the capability to move and metastasize from the primary tumour. Thus, understanding the switch function enable the creation of drug that controls cancer cell metastasis and tissue fibrosis. EMT, epithelial to mesenchymal transition, is vital during the development of embryos but not in adult, because when it is reactivated, it will leads to cancer cell evolement.
The master-switch, known as Epithelial Splicing Regulatory Protein, divided into 2 types, ESRP1 and ESRP2. These proteins will splice different exons on an RNAs and the end result will be different type of RNAs are produced from the same particular gene which carried forward in synthesizing different proteins.
The mRNA for Fibroblast Growth Factor Receptor 2 (FGFR2) has two forms, one called IIIb, which is expressed in epithelial cells and IIIc, which is expressed in mesenchymal cells. IIIb ensure the epithelial cells remain stationary while IIIc promotes epithelial cell to gain mesenchymal cell's characteristics such as moving from primary sites, invade other cells and metastasize in other part of the body.
“If we can find a way to maintain expression of ESRP1 and 2 in epithelial cells, then it might be possible to prevent metastasis or control fibrosis,” notes corresponding author Russ P. Carstens, MD, Assistant Professor of Medicine. “ESRP1 and ESRP2 are necessary for splicing FGFR2 mRNA in the epithelial cell manner. This is one of few known splicing factors that operate in a clear cut cell-type-specific manner. Epithelial cells, which make up the lining of organs, are the only cells that produce ESRP1 and ESRP2.”
In short, ESRP 1 an 2 control the expression of FGFR2 in IIIb manner and prevent IIIc manner. Knockdown of of both ESRP1 and ESRP2 in an epithelial cell line caused a switch in endogenous FGFR2 splicing toward the mesenchymal pathway
University of Pennsylvania School of Medicine (2009, March 17). Master Molecular Switch May Prevent The Spread Of Cancer Cells To Distant Sites In The Body. ScienceDaily. Retrieved March 18, 2009, from http://www.sciencedaily.com /releases/2009/03/090316133436.htm
Claude C. Warzecha, Trey K. Sato, Behnam Nabet, John B. Hogenesch, and Russ P. Carstens (2009). ESRP1 and ESRP2 Are Epithelial Cell-Type-Specific Regulators of FGFR2 Splicing. Molecular Cell 33, 591–601. Accessed on 18 March 2009. Retrieved from http://download.cell.com/molecular-cell/pdf/PIIS1097276509000690.pdf?intermediate=true
