Medulloblastomas represent about 25 percent of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum and affect mainly children between ages five and fifteen. Although the etiology of medulloblastoma remains unknown, several reports suggest that insulin-like growth factor I (IGF-1) may contribute to the development of these tumors. Our recent studies revealed the presence of the phosphorylated (active) IGF-I receptor (IGF-IR) in more than half of human medulloblastoma biopsies examined. The major IGF-IR signaling molecule, insulin receptor substrate 1 (IRS-1) is strongly overexpressed in these tumors, and the IRS-1 translocation to the nucleus has been observed exclusively in JCV T-antigen positive medulloblastoma cell lines, and in JCV T- antigen positive human medulloblastoma biopsies. A transgenic animal model utilizing the JC virus (JCV) early genome provides an experimental system, in which the IRS-1 could be actually studied in medulloblastomas. These mice develop spontaneous cerebellar tumors that histologically are close parallels to human medulloblastomas. The early genome of this virus encodes regulatory protein, JCV T-antigen, that has transforming properties in cell culture, and is tumorogenic in experimental animals. Interestingly, recent studies revealed association of JCV genome with spontaneous medulloblastomas in humans, and the expression of JCV T-antigen in some but not all human tumor cells. This is comparable with the observation in transgenic mouse model where not all medulloblastoma cells containing JCV early genome, express T-antigen. Although a cause and effect relationship between JCV T-antigen and human medulloblastoma remains to be established, the availability of JCV T-antigen positive and negative medulloblastoma cell lines provides an unique experimental system, in which the role of IRS-1 nuclear translocation could be studied in a different T-antigen context.
Three specific aims are proposed to test the hypothesis that IRS- 1 nuclear translocation contributes to the malignant growth in medulloblastoma. In the first aim, mutational analysis of the IRS-1 and JCV T-antigen will be applied to determine binding domains involved in the physical interaction between these two molecules. In the second aim, by targeting IRS-1 and JCV T- antigen binding sites we will develop new dominant negative mutants capable of interfering with the IRS-1- JCV T-antigen binding. These new mutants will be tested in both JCV T-antigen positive and negative medulloblastoma cell lines to determine whether the IRS-1 - JCV T-antigen interaction contributes to the transformed phenotype in medulloblastomas. Finally in the third aim, we will characterize biological significance of the JCV T- antigen -mediated translocalization of IRS-1 into the nucleus, and determine whether targeted disruption of the IRS-1 - JCV T- antigen interaction attenuates the development and/or progression of primitive neuroectodermal tumors/medulloblastomas in experimental animals.
| Lassak, Adam; Dean, Mathew; Wyczechowska, Dorota et al. (2018) Molecular and Structural Traits of Insulin Receptor Substrate 1/LC3 Nuclear Structures and Their Role in Autophagy Control and Tumor Cell Survival. Mol Cell Biol 38: |
| Grabacka, M; Waligorski, P; Zapata, A et al. (2015) Fenofibrate subcellular distribution as a rationale for the intracranial delivery through biodegradable carrier. J Physiol Pharmacol 66:233-47 |
| Jeansonne, Duane; DeLuca, Mariacristina; Marrero, Luis et al. (2015) Anti-tumoral effects of miR-3189-3p in glioblastoma. J Biol Chem 290:8067-80 |
| Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E et al. (2014) Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma. Neoplasia 16:874-82 |
| Wilk, Anna; Waligórski, Piotr; Lassak, Adam et al. (2013) Polycyclic aromatic hydrocarbons-induced ROS accumulation enhances mutagenic potential of T-antigen from human polyomavirus JC. J Cell Physiol 228:2127-38 |
| Jeansonne, Duane; Pacifici, Marco; Lassak, Adam et al. (2013) Differential Effects of MicroRNAs on Glioblastoma Growth and Migration. Genes (Basel) 4:46-64 |
| Grabacka, Maja; Pierzchalska, Malgorzata; Reiss, Krzysztof (2013) Peroxisome proliferator activated receptor ? ligands as anticancer drugs targeting mitochondrial metabolism. Curr Pharm Biotechnol 14:342-56 |
| Reiss, Krzysztof; Del Valle, Luis; Lassak, Adam et al. (2012) Nuclear IRS-1 and cancer. J Cell Physiol 227:2992-3000 |
| Vashistha, Himanshu; Singhal, Pravin C; Malhotra, Ashwani et al. (2012) Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney. Am J Physiol Renal Physiol 303:F1629-40 |
| Prakash, O; Lukiw, W J; Peruzzi, F et al. (2012) Gliomas and seizures. Med Hypotheses 79:622-6 |
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