3 edition of DJ-1 regulates tumour suppression by PTEN and cellular responses to oxidative stress in Parkinson"s disease found in the catalog.
DJ-1 regulates tumour suppression by PTEN and cellular responses to oxidative stress in Parkinson"s disease
Raymond H. Kim
Written in English
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.
|Statement||by Raymond H. Kim.|
|The Physical Object|
|Number of Pages||225|
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