Peter Stoilov, Ph.D.
MSc: Sofia University, Sofia, Bulgaria
PhD: Friedrich-Alexander-University, Erlangen, Germany
Postdoctoral training: University of California Los Angeles
Joined the faculty: 2010
Office: 3080I HSN
Phone: (304) 293-6334
Fax: (304) 293-6846
Regulation of alternative pre-mRNA splicing; Alternative splicing in cancer progression; Drugs targeting alternative splicing as cancer therapeutics and research tools; High-throughput research methods.
Pre-mRNA splicing and disease:
The majority of eukaryotic genes are split into alternating exon and intron sequences. During the pre-mRNA maturation the introns are excised from the transcripts and the exons are spliced together. Frequently, in a process known as alternative pre-mRNA splicing, multiple mRNAs variants are generated from a single gene by skipping or including certain exons. Alternative splicing plays a significant role in generating enormous protein diversity from the limited number of genes in the eukaryotic genomes. It is also an important control point for gene expression and protein function, that is regulated during development and by various physiological processes.
Disruption and misregulation of pre-mRNA splicing are a major cause of disease in humans. Estimated 50% of disease causing mutations affect pre-mRNA splicing. Alternative splicing has been identified as therapeutic target in various pathological conditions including neurodegenerative diseases, autoimmune disorders, retroviral infections and cancer. Several recent studies show that on a global scale tumors share similar alternative splicing patterns that are distinct from those of the tissues of origin. This shift in alternative splicing adjusts the properties of multiple proteins resulting in a broad effect on the tumor physiology. Notable examples are protein isoforms with anti-apoptotic properties (Bin1, Bcl-XL), growth factor receptors with increased sensitivity and/or altered specificity (FGFR1 and 2), and enzymes that redirect metabolites from energy production to anabolic processes (PKM2). As a result drugs modulating alternative splicing can provide a new therapeutic approach that will simultaneously impact multiple molecular targets and be effective on cancers of various types and origins.
Identify alternative splicing events that are critical for cancer progression. We have successfully used genetic approaches, such as microarrays and RNA knockdown, to characterize the role alternative splicing plays in neuronal development. Now I plan to use these techniques as well as deep sequencing and genetic screens to investigate the role alternative splicing plays in cancer. In particular I am interested in identify alternative splicing events that are critical for cancer progression and dissecting the molecular mechanism that control them.
Develop novel cancer therapeutics that target alternative splicing. In my most recent work I developed a fluorescent reporter that can be used to monitor the splicing of alternative exons in living cells. This reporter was used in high-throughput screening of compound libraries to identify over a hundred small molecules capable of modulating alternative splicing. Interestingly some of these compounds can correct the splicing of the PKM2 transcript that is critical for cancer cell growth. The compounds targeting PKM2 splicing are now being used as leads for developing anticancer drugs. The splicing reporter is also being employed to screen for more compounds that target alternative exons with known roles in cancer, such as PKM2 M1/M2, FGFR2 IIIb/IIIc, FGFR1-alpha.
Lauren T. Gehman, Peter Stoilov, Jamie Maguire, Andrey Damianov, Chia-Ho Lin, Lily Shiue, Manuel Ares Jr., Istvan Mody, and Douglas L. Black (2011) "The splicing regulator Fox-1/A2BP1 controls neuronal excitation in the mammalian brain"., Nature Genetics, Accepted for publication.
Stoilov P (2011) Chapter 46: 'Screening for Alternative Splicing Modulators', in 'Alternative pre-mRNA Splicing Theory and Protocols', editors Stamm S., Chris, S., Luhrmann R., ISBN-10: 3-527-32606-5, Wiley-VCH, In press
Stoilov P. Screening for alternative splicing modulators. in "RNA splicing: The complete guide", edited by Stefan Stamm, Christopher Smith and Reinhard Luehrmann. 2010 in press
Stoilov P., Lin CH, Damoiseaux R, Nikolic J, Black DL. A new high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators. PNAS. 2008 Aug 12;105(32):11218-23
Xing Y, Stoilov P., Kapur K, Han A, Jiang H, Shen S, Black DL, Wong WH. MADS: A new and improved method for analysis of differential alternative splicing by exon-tiling microarrays. RNA. 2008 Aug 1;14(8):1470-1479.
Boutz PL*, Stoilov P.*, Li Q, Lin CH, Chawla G, Ostrow K, Shiue L, Ares M Jr, Black DL. A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev. 2007 Jul 1;21(13):1636-52. (*authors with equal contribution)