Numerous pathological conditions result from dysfunction in the central nervous system. These include diseases such as Parkinson's and Huntington's as well as malignant tumors including glioma and oligodendroglioma. The identification of adult neural stem cells has suggested that their longevity and proliferative potential may help to identify a cell of origin for such tumors as well as therapies for neurodegenerative disorders. Recently, the observation that neural progenitors from Tp53 null (-/-) mice grow more rapidly than their wildtype counterparts and after DNA damage fail to down regulate expression of Id2, a transcription factor known to inhibit the activation of genes regulated by basic helix-loop-helix transcription factors. I hypothesize that Tp53 has a key role in regulating the proliferation of adult neural stem cells, and if inactivated can contribute to the genetic instability of the cells and possibly tumorigenesis. Preliminary data suggests that sustained Id2 expression resulting from the loss of functional Tp53 contributes to both the radiation resistance of gliomas and the increased growth rate of Tp53 null progenitor cells. I will test if this enhanced proliferation is the result of Id2 over-expression and seek to better understand the mechanism of Id2 repression by Tp53. These experiments will be conducted in neural stem cells as they may behave like, or even be the cell type in which glial tumors arise. Also, since loss of the G1 arrest following DNA damage by therapeutic irradiation is thought to contribute to the resistance of cells to this modality of treatment, I will examine whether this resistance is mediated by Id2, which preliminary studies suggest to be a direct target of Tp53. Furthermore, recently published experiments from other laboratories have demonstrated that radiation resistant glioma cells express enhanced stem like properties. A hypothesis that might explain this observation is that radiotherapy may select for stem-like cells with defective p53 function. This proposal is aimed at identifying a novel Tp53 target, Id2, that is a credible mediator of Tp53 cell cycle inhibition and as such a contributor to tumorigenesis and a potential therapeutic target for enhancing the radio sensitivity glioma treatment. The adult brain contains neural stem cells that are potentially linked as the origin of brain tumors. This proposal is aimed at understanding the effect of Id2, a novel Tp53 target and its role in radiation resistant gliomas. This research is directly relevant to understanding and developing new treatments for brain tumors.
| Sullivan, Jaclyn M; Havrda, Matthew C; Kettenbach, Arminja N et al. (2016) Phosphorylation Regulates Id2 Degradation and Mediates the Proliferation of Neural Precursor Cells. Stem Cells 34:1321-31 |
| Havrda, Matthew C; Paolella, Brenton R; Ran, Cong et al. (2014) Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment. Cancer Res 74:1822-32 |
| Havrda, Matthew C; Paolella, Brenton R; Ward, Nora M et al. (2013) Behavioral abnormalities and Parkinson's-like histological changes resulting from Id2 inactivation in mice. Dis Model Mech 6:819-27 |
| Paolella, Brenton R; Havrda, Matthew C; Mantani, Akio et al. (2011) p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells. Stem Cells 29:1090-101 |
