Regulation of PI3'K signaling by Grb2 and TACC1.
Published: 2005
Language: eng
Number of pages: 191
Description: The Ras and phosphatidylinositol 3' kinase (PI3'K) signaling pathways are critical mediators of cellular proliferation and cell survival. Mutations in both of these pathways are commonly found in both spontaneous tumors and syndromes of cancer predisposition. PTEN, a negative regulator of PI3'K signaling, is a tumor suppressor associated with human breast cancer, gliomas, and other malignancies. Mice homozygous for a null mutation in pten die during embryogenesis. There are numerous mechanisms for activating PI3'K, including physical interaction between Ras and PI3'K. To determine the physiological significance of alternative mechanisms for PI3'K activation, mice heterozygous for pten were crossed with mice heterozygous for the Ras pathway adaptor molecule grb2. Grb2 acts upstream of Ras activation in the response to external growth factors. In addition, Grb2 can activate PI3'K in a Ras-independent manner through Gab1. While grb2  heterozygosity had no effect on tumorigenesis in pten +/- mice, grb2 heterozygosity completely rescued  pten+/- embryonic lethality. This previously uncharacterized lethality is associated with defects in both embryonic and extraembryonic tissues. Fibroblasts with reduced levels of Grb2 are hypersensitive to death induced by growth factor withdrawal and exhibit attenuated Erk and PKB activation in response to epidermal growth factor treatment. Both of the characteristics are reversed by ectopic expression of Grb2 or Grb2 lacking the N- but not C-terminal SH3 domain. Grb2-dependent mechanisms of PI3'K activation are essential to embryonic development. The C-terminal SH3 domain of Grb2 is required for signaling to PI3'K in fibroblasts.TACC1 (transforming acid coiled coil) also affects PI3'K and Ras signaling. TACC1 protects cells from death induced by PI3'K pathway blockade. TACC1 cooperates with Ras in transformation. Mice that express TACC1 from the MMTV promoter were generated. These mice show elevated activation of both Erk and PKB signaling pathways. Furthermore, apoptosis is decreased in these mice during mammary gland involution, a phenotype previously reported in mice transgenic for  MMTV/PKB. Mice doubly transgenic for MMTV/TACC1 and MMTV/PyMT315/322 exhibit an increased risk of tumorigenesis when compared to mice transgenic for MMTV/PyMT315/322 alone. These data suggest that TACC1 plays an important role in Ras and PI3'K signaling and tumorigenesis.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5209.

Thesis (Ph.D.)--University of Toronto, 2005.

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