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.
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