Characterization of physiological Pten function in the brain, skin and prostate using tissue-specific knockout mice.
Published: 2004
Language: eng
Number of pages: 216
Description: PTEN is a tumour suppressor gene mutated in a wide spectrum of human cancers. Individuals with a germline mutation in PTEN develop an autosomal dominant multiple hamartoma syndrome called Cowden's disease and are highly susceptible to malignancies. PTEN is a 3'-specific phosphatidylinositol (3,4,5) trisphosphate phosphatase and functions as a negative regulator of cellular survival and proliferation mediated by phosphatidylinositol 3'kinase-protein kinase B/Akt signaling. Deletion of pten in mice results in embryonic lethality, whereas animals heterozygous for this gene have a high incidence of tumors in multiple tissues. However, skin and brain growths characteristic of Cowden's disease and related hamartoma conditions such as Lhermitte-Duclos disease were not represented in pten +/- animals. In addition, while advanced prostate carcinomas frequently harbour PTEN mutations in humans, prostate tumours in pten+/- mice had a prolonged latency and were rarely malignant. Using the Cre-loxP system, tissue-specific deletion of both pten alleles was conducted in the mouse to study this gene's role in development and tumorigenesis of the brain, skin and prostate. Deletion of pten in the murine brain resulted in neurological symptoms and abnormalities similar to those of Lhermitte-Duclos disease patients including seizures, ataxia, premature death and cerebellar lesions. pten mutant brains were enlarged as a consequence of increased neuron size, representing the first evidence for the role of Pten in mammalian cell size regulation. Inactivation of Pten in the skin and prostate resulted in overgrowth of these tissues with early onset and complete penetrance. pten mutant mice developed palmoplantar skin lesions similar to those of Cowden patients and high-grade prostatic intraepithelial neoplasia that progressed to invasive adenocarcinoma. Overgrowth of these epithelial tissues was the result of increased proliferation and, in the prostate, increased cell size. These analyses indicate that Pten is an important regulator of proliferation in the skin and a critical tumour suppressor in the prostate. Together, these studies and work from others demonstrate that Pten is an important physiological regulator of organ growth through effects on cell size and cell division. Further, Pten function and the severity of pathological consequences that ensue upon deletion of this gene appear to be tissue-specific in nature.
Notes: Adviser:  Tak W. Mak.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4959.