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Principal Investigator: Dawn S Chandler
Organization: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
Fiscal Year: 2024
Award: $63,326
Funding agency: National Cancer Institute
ABSTRACT
Tumor suppressor p53 is the quintessential guardian of the genome whose function is inhibited in greater than
50% of all human cancers. Though mutation and deletion of p53 are major contributors to p53 inactivation,
overexpression of the negative regulators MDM2 and MDM4 (MDMX) are also known to inactivate p53, thus
leading to the cancer phenotype. Our lab has shown that specific types of cell stress initiate the generation of
an alternatively spliced isoform of MDM2. The predominant MDM2 alternative isoform, MDM2-ALT1 also
known as MDM2-B, functions to primarily activate the p53 pathway by inhibiting MDM2 and MDM4 in a
dominant negative fashion. Paradoxically, this isoform is upregulated in several human cancers, such as
pediatric high-grade gliomas, astrocytomas, rhabdomyosarcomas (RMS), and liposarcomas, as well as adult
cancers such as lymphomas and those of the breast. Thus, MDM2-ALT1 plays opposing roles in cancer
progression dependent upon the context of its expression. In the proposed research, we will study the
underpinnings of the control of the p53 pathway by MDM2-ALT1 to better understand 1) the specific
mechanism by which that MDM2-ALT1 is generated in cancer and 2) the ability of the resultant isoforms to be
targeted using splice-switching oligonucleotides. We hypothesize that the expression of oncogenic MDM2-
ALT1 is modulated by alterations in protein and RNA nuclear factors during the progression to tumorigenesis
and can be targeted to induce splicing changes. We will use assays that identify and measure splice regulation
in conjunction with gene editing approaches to identify RNA sequences and their respective nuclear factor-
binding partners necessary for regulation of MDM2 splicing. Furthermore, we will use novel genetically
engineered mouse models as well as established mouse xenograft assays and novel splice switching
oligonucleotides (SSOs) to modulate MDM2 isoform levels. Our work will broaden our knowledge of
combinatorial regulation of RNA processing in response to stress and in cancer and interrogate the utility of
MDM2 isoforms modulation for rational control of the p53 pathway.
Terms: <21+ years old><ALT1><Abscission><Adult><Adult Human><Alanine Aminotransferase><Alanine Transaminase><Alanine-2-Oxoglutarate Aminotransferase><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Anti-Cancer Agents><Antimorphic mutation><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antioncogene Protein p53><Assay><Astrocytic Glioma><Astrocytic Neoplasm><Astrocytic Tumor><Astrocytoma><Astroglioma><Automobile Driving><Binding><Binding Proteins><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biology><Biophysics><Breast><Cancer Biology><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><CellLine><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Cellular Stress><Cellular Stress Response><Cellular Tumor Antigen P53><Chemistry><Childhood Cancers><Childhood Glioma><Complex><Coupled><DNA Damage><DNA Injury><Data><Disease><Disorder><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Engineering><Event><Excision><Exons><Extirpation><Future><GEM model><GEMM model><Generations><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Genome><Genotoxic Stress><Germinoblastic Sarcoma><Germinoblastoma><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Glutamic-Alanine Transaminase><Glutamic-Pyruvate Transaminase><Glutamic-Pyruvic Transaminase><Goals><HDM2><Heterograft><Heterologous Transplantation><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Human><In Vitro><Isoforms><Knowledge><Length><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Respiratory System><Lymphoma><MDM2><MDM2 gene><MDMX protein><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Lymphoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Mdm-2 protein><Measures><Mechanics><Mediating><Methodology><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Neoplastic Disease Chemotherapeutic Agents><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Nuclear><Nuclear Protein><Nuclear RNA><Nucleic Acid Biochemistry, RNA - Ribonucleic Acid><Oligo><Oligonucleotides><Oncogenesis><Oncogenic><Oncoprotein MDM2><Oncoprotein p53><Outcome><Ovary><P53><Pathway interactions><Pediatric Glioma><Pediatric high-grade glioma><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Play><Position><Positioning Attribute><Pre-mRNA><Primary Neoplasm><Primary Tumor><Property><Protein Binding><Protein Isoforms><Protein TP53><Proteins><Publishing><RNA><RNA Biochemistry><RNA Gene Products><RNA Nucleic Acid Biochemistry><RNA Processing><RNA Sequences><RNA Splicing><RNA metabolism><RNA, Messenger, Precursors><RNA-Binding Proteins><Regulation><Regulatory Element><Removal><Repression><Research><Reticulolymphosarcoma><Rhabdomyosarcoma><Ribonucleic Acid><Role><Sampling><Splicing><Strains Cell Lines><Stress><Surgical Removal><System><TP53><TP53 gene><TRP53><Technology><Testing><Therapeutic><Therapeutic Intervention><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><Tumor-Specific Treatment Agents><Variant><Variation><Viral><Work><Xenograft><Xenograft procedure><Xenotransplantation><adulthood><anti-cancer drug><anti-cancer therapy><biophysical foundation><biophysical principles><biophysical sciences><bound protein><cancer in a child><cancer in children><cancer progression><cancer therapy><cancer type><cancer-directed therapy><cell growth><cell stress><cell type><chemotherapeutic agent><child with cancer><childhood malignancy><combinatorial><cultured cell line><design><designing><driving><drug discovery><exon skipping><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene-editing approach><genetically engineered mouse model><genetically engineered murine model><genome mutation><genotoxicity><glial-derived tumor><industrial partnership><industry partner><industry partnership><intervention design><intervention therapy><liposarcoma><mRNA Precursor><malignancy><mdm-2 oncogene protein><mdm2 protein><mechanic><mechanical><miRNA><miRNAs><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><neuroglia neoplasm><neuroglia tumor><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oligos><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><p53-Binding Protein MDM2><pathway><pediatric cancer><pediatric malignancy><pharmaceutical><prevent><preventing><protein p53><pulmonary><resection><response><social role><therapy design><treatment design><tumor><tumor progression><tumor suppressor><tumorigenesis><tumorigenic><xeno-transplant><xeno-transplantation>