FTEN was identified as a candidate tumor-suppressor gene on chromosome band 10q23, a genomic region deleted in a larger number of tumors. The gene encodes a dual-specificity phosphatase, and is mutated in a variety of human cancers. The applicant hypothesizes that PTEN may behave as a tumor/growth suppressor. He proposes to unravel the mechanisms by which PTEN would suppress tumorigenesis and regulate embryonic development through a direct genetic approach.
The specific aims are: 1. To define, in knock-out mice, the role of Pten in ontogenesis. He will elucidate the causes underlying aberrant embryogenesis in the absence of Pten, and he will generate conditional Pten mutants via a Cre-loxP mediated approach. 2. To establish in knock-out mice or derived null cells, the role of Pten in oncogenesis, tumor initiation, promotion and progression. He will examine spontaneous or physically/chemically induced turmorigenesis, tumor initiation, promotion and progression in Pten+/- mutants, or in somatic chimeras generated from ES cells in which Pten has been disrupted by double homologous recombination, as well as in tissue specific Pten-/- mutants. To determine if Pten loss cooperates with the transforming ability of known oncogenes, he will assess tumorignenesis in Pten+/- p27Kip1-/- mice; Pten+/- p53-/- mice, Pten+/- Apc+/- mice and Pten+/- mice overexpressing the v-Src proto-oncogene. 3. To establish, in knock out mice or Pten null cells, the role of Pten in controlling cell survival and adhesion through PI3-Kinase and Focal Adhesion signaling pathways. To identify target genes of Pten which may be important for these pathways, he will screen cDNA expression arrays with cDNA probes generated from mRNAs obtained from Pten+/+ and Pten-/- cells.
| van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige et al. (2017) Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation. Mol Cancer Ther 16:1279-1289 |
| Matsumoto, Akinobu; Pasut, Alessandra; Matsumoto, Masaki et al. (2017) mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541:228-232 |
| Noguera, Nélida Inés; Piredda, Maria Liliana; Taulli, Riccardo et al. (2016) PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity. Oncotarget 7:66386-66397 |
| Tay, Yvonne; Pandolfi, Pier Paolo (2016) Posttranscriptional Regulation of PTEN by Competing Endogenous RNAs. Methods Mol Biol 1388:139-54 |
| Lunardi, Andrea; Varmeh, Shohreh; Chen, Ming et al. (2015) Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov 5:550-63 |
| Poliseno, Laura; Pandolfi, Pier Paolo (2015) PTEN ceRNA networks in human cancer. Methods 77-78:41-50 |
| Tay, Yvonne; Rinn, John; Pandolfi, Pier Paolo (2014) The multilayered complexity of ceRNA crosstalk and competition. Nature 505:344-52 |
| González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904 |
| Song, Su Jung; Pandolfi, Pier Paolo (2014) miR-22 in tumorigenesis. Cell Cycle 13:11-2 |
| Tay, Yvonne; Tan, Shen Mynn; Karreth, Florian A et al. (2014) Characterization of dual PTEN and p53-targeting microRNAs identifies microRNA-638/Dnm2 as a two-hit oncogenic locus. Cell Rep 8:714-22 |
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