Loss or mutation of the p53 tumor suppressor gene is thought to be an important event in the malignant transformation of human astrocytes. The loss of wild-type p53 function may render cells more susceptible to genetic instability, predisposing them to neoplastic transformation. However, the specific genetic alterations that occur in astrocytes following the loss of p53 function have not been defined. Using glass- based high-density cDNA arrays we identified a novel gene that was significantly upregulated in malignant mouse astrocytes relative to normal mouse astrocytes. This gene was identified as pescadillo, which was first characterized as a gene that was essential for embryonic development in zebrafish. A yeast homologue of pescadillo has also been identified and its deletion is lethal in yeast. Preliminary data from our laboratory has shown that the pescadillo protein is highly expressed in human brain tumor cells suggesting that it may represent an important molecular change in human glial tumors. Although pescadillo contains several significant structural motifs including the presence of a BRCA1 carboxy terminus domain, its function and its relationship to malignancy remain unknown.
The aim of the present proposal is to characterize the biochemical function and the cellular role of pescadillo in normal and malignant astrocytes. We will: 1) Determine if the pescadillo protein is abnormally expressed in human glial tumors; 2) Determine if pescadillo regulates the proliferation and invasiveness of normal and malignant astrocytes; 3) Determine if pescadillo regulates the cellular response of astrocytes to DNA damage and alters their sensitivity to chemotherapeutic agents; and 4) Characterize the biochemical function of pescadillo by analyzing its binding partners using a yeast two hybrid and proteomics screen. Since pescadillo represents a novel gene whose activity is essential for yeast viability and zebrafish development, elucidating its cellular role may provide unique insights into the process of neoplastic transformation and may provide a new target for suppressing the growth of human brain tumors.
| Sikorski, Eric M; Uo, Takuma; Morrison, Richard S et al. (2006) Pescadillo interacts with the cadmium response element of the human heme oxygenase-1 promoter in renal epithelial cells. J Biol Chem 281:24423-30 |
| Elias, Maria C; Tozer, Kathleen R; Silber, John R et al. (2005) TWIST is expressed in human gliomas and promotes invasion. Neoplasia 7:824-37 |
| Morrison, Richard S; Kinoshita, Yoshito; Johnson, Mark D et al. (2002) Proteomic analysis in the neurosciences. Mol Cell Proteomics 1:553-60 |
