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Principal Investigator: Dinesh S. Rao
Organization: UNIVERSITY OF CALIFORNIA SANTA CRUZ
Fiscal Year: 2024
Award: $580,298
Funding agency: National Cancer Institute
PROJECT SUMMARY/ ABSTRACT
Protein-RNA interactions underlie an important and understudied component of gene regulation. RNA-binding
proteins carry out numerous functions relating to the production, splicing, processing, and stability of mRNA
molecules. A few years ago, we discovered that the oncofetal RNA binding protein, IGF2BP3, binds to the 3’
untranslated region of mRNA and regulates mRNA stability via a mechanism that involves the RNA-induced
silencing complex. In more recent work, we found that IGF2BP3 also binds near 3’-splice sites, and may
regulate alternative splicing. Together, our findings suggest dual roles in mRNA regulation for IGF2BP3.
IGF2BP3 regulates genes that are related to proliferation, migration, and signaling- which are important in fetal
development- but also in cancer. Concordant with this gene regulatory function, IGF2BP3 is overexpressed in a
wide range of malignancies, including acute leukemia, and portends a poor prognosis when highly expressed.
Using novel, murine genetic models of IGF2BP3 deficiency, we have now discovered that IGF2BP3 is required
for the development of a fully-penetrant, lethal leukemia in vivo. Together, our extensive prior work, both
published and unpublished, provides a mechanistic framework for its function, and a solid foundation for the
importance of this protein in disease. To fully understand the nature of these protein-RNA interactions and to
understand their role in cancer, we propose two aims. In the first aim, we will carefully delineate the mechanism
underlying IGF2BP3 function by a combination of carefully executed experiments (Aim 1). In the second aim,
we will characterize the importance of IGF2BP3 in leukemia initiation, propagation and maintenance using a set
of carefully constructed genetic models and gene editing in primary cells. Next, we will characterize how the two
proposed gene regulatory mechanisms- RNA stability and pre-mRNA splicing- play roles in cancer initiation,
using a combination of reverse genetics, miRNA regulation, and isoform specific expression. Together, this work
will lead to a layered, detailed understanding of how mechanistic basis of protein-RNA interactions is intimately
connected to gene expression deregulation and the malignant transformation of cells. Importantly, it will pave
the way to develop novel diagnostic and therapeutic approaches in malignancies characterized by massive
transcriptomic dysregulation underpinned by alterations of RNA-binding proteins.
Terms: <3' Splice Site><3' Untranslated Regions><3'UTR><Acute leukemia><Aggression><Aggressive behavior><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Assay><BP2><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Binding Sites><Bioassay><Biological Assay><Biology><Cancer Biology><Cancers><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chimera Protein><Chimeric Proteins><Combining Site><Competitive Binding><DNA Molecular Biology><Data><Developing fetus><Development><Diagnostic><Disease><Disorder><Equilibrium><Etiology><Fetal Development><Foundations><Functional RNA><Fusion Protein><Gene Action Regulation><Gene Combinations><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Models><Genetic defect><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Human><IBP2><IGF-2><IGF-BP53><IGF-II><IGFBP2><IGFBP2 gene><Immune Precipitation><Immunoprecipitation><In Situ><In Vitro><Insulin-Like Growth Factor 2><Insulin-Like Growth Factor Binding Protein 2><Insulin-Like Growth Factor II><Insulin-Like Somatomedin Peptide II><Intracellular Communication and Signaling><Investigation><Isoforms><Knock-out><Knockout><Knowledge><Leukemic progenitor and stem cell><Ligand Binding Protein><Ligand Binding Protein Gene><Maintenance><Malignant><Malignant - descriptor><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Measurement><Mediating><Mediator><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Molecular Biology><Molecular Interaction><Multiplication-Stimulating Activity><Multiplication-Stimulating Factor><Murine><Mus><Mutation><Nature><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Oncogenesis><Oncogenic><Oncology><Oncology Cancer><Pathogenesis><Play><Post-Transcriptional Control><Post-Transcriptional Regulation><Pre-mRNA><Production><Progenitor Cells><Prognosis><Proliferating><Protein Binding><Protein Isoforms><Proteins><Public Health><Publishing><RISC Multicomponent Nuclease><RNA><RNA Gene Products><RNA Splice Sites><RNA Splicing><RNA Stability><RNA and protein interaction><RNA, Messenger, Precursors><RNA-Binding Proteins><RNA-Induced Silencing Complex><RNA-Protein Interaction><Reactive Site><Regulation><Regulator Genes><Reporter><Research><Resistance><Ribonucleic Acid><Role><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Site><Solid><Somatomedin A><Somatomedin MSA><Splice Acceptor Sites><Splicing><Structure><Testing><Therapeutic><Transcript><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Translating><Translations><Untranslated RNA><Work><balance><balance function><biological signal transduction><bound protein><cancer initiation><cancer type><causation><cell transformation><clinical translation><clinically translatable><competitively bound><conditional knock-out><conditional knockout><crosslink><developmental><diagnostic ability><diagnostic capability><diagnostic power><diagnostic utility><diagnostic value><disease causation><experiment><experimental research><experimental study><experiments><genetic approach><genetic strategy><genome mutation><in vivo><insight><insulin regulation><leukemia><leukemic progenitor><leukemic stem cell><mRNA><mRNA Precursor><mRNA Stability><malignancy><miRNA><miRNAs><migration><neoplasm/cancer><new diagnostics><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><next generation diagnostics><noncoding><novel><novel diagnostics><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><prognostic><regulatory gene><resistance to therapy><resistant><resistant to therapy><reverse genetics><social role><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic target><therapy resistant><trans acting element><transcription factor><transcriptomics><transformed cells><translation><treatment resistance><tumorigenesis>