DJ-1 regulates tumour suppression by PTEN and cellular responses to oxidative stress in Parkinson's disease
By: by Raymond H. Kim.
Published: 2006
Language: eng
Number of pages: 225
ISBN-13: 9780494160176
Description: The cell survival pathway mediated by phosphatidylinositol 3' kinase (PI3'K) and its downstream effector protein kinase B (PKB/Akt) is crucial for many developmental processes. The tumour suppressor gene PTEN negatively regulates this pathway, however the regulation of PTEN itself is not well characterized. Using a Drosophila-based genetic screen to identify genes that modulate PTEN activity, we isolated the DJ-1 gene as a putative negative regulator of PTEN. The mammalian orthologue of this gene protected against various cellular insults in a PTEN-dependent manner through activation of the PI3'K-PKB/Akt signaling pathway. Profiling of the transcripts and proteins expressed in samples from lung and breast cancer patients indicated that DJ-1 expression correlated with high levels of PKB/Akt activation and in breast cancers, low PTEN expression, implying that DJ-1 has an epigenetic effect on PTEN function. Furthermore, a higher level of DJ-1 transcripts in tumour tissues of non-small cell lung cancer patients correlated with a poor prognosis, suggesting a novel role for DJ-1 as a molecular marker of aggressive cancers. Concurrent with our characterization of DJ-1 as a gene involved in PTEN regulation and tumorigenesis, others identified loss-of-function mutations in the DJ-1 locus in patients with autosomal recessive, early-onset Parkinson's disease. To examine this phenomenon and to clarify the physiological role of DJ-l, DJ-1 deficient mice were generated by gene-targeting.	DJ-1 knockout (DJ-1-/-) mice were viable and fertile and did not show any gross or neuronal abnormalities. However, neurons cultured from DJ-1 -/- mice were abnormally susceptible to oxidative (but not non-oxidative) insults. Significantly, DJ-1-/- mice were hypersensitive to the Parkinsonian neurotoxin 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), showing increased neuronal degeneration in the substantia nigra and striatum. Adenovirus-mediated introduction of the wild type DJ-1 gene into DJ-1-/- mice resulted in protection against toxin-induced neurodegeneration and rescued the susceptibility of these animals to MPTP. The two complementary studies on DJ-1 function embodied in this thesis have demonstrated the role of the regulator DJ-1 in normal cell survival and death pathways, and in the pathological processes of tumorigenesis and neurogeneration.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3647.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

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