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Ectopic Expression of Copper-Zinc Superoxide Dismutase Attenuates the Tumorigenicity of SK-Hep-1 Hepatoma CellsLin, I-Chun 28 August 2007 (has links)
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in
Taiwan. Copper-zinc superoxide dismutase (SOD1) is widely distributed and
comprises 90% of the total superoxide dismutase (SOD), which catalyzes the
conversion of superoxide to hydrogen peroxide. Reduced expression of
antioxidant enzymes, particularly SOD1, has been identified in human
hepatoma specimens and cell lines. However, it remains unclear how SOD1
expression affected the tumorigenic processes of hepatoma cells. Expression
analysis of an array of human HCC cell lines revealed that SOD1 protein
levels were down regulated in poorly differentiated SK-Hep-1 cells.
Adenovirus-mediated SOD1 expression increased the SOD1 protein level by
30-40% of control. In addition, SOD1 gene transfer decreased the cellular
O2
¡V level yet increased the H2O2 production. SOD1 overexpression
significantly reduced the proliferation, motility, and anchorage-independent
growth of SK-Hep-1 cells, but had no effect on the secretion of matrix
metalloproteinase-2 (MMP-2) and MMP-9. SOD1 restoration inhibited the
proliferation of SK-Hep-1 cells through induction of cell cycle arrest, which
was associated with decreased expression of cyclin A, cyclin D1, cdk1, cdk4
and upregulation of p21Cip1 and p27kip1. Besides, SOD1 overexpression also
inhibited the nuclear factor £e B (NF-£eB) activities, thereby attenuating the
proliferation and migration of SK-Hep-1 cells. In conclusion, SOD1
restoration attenuated the tumorigenicity of hepatoma cells.
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Stability and aggregation propensities of ALS-associated human superoxide dismutase mutantsTong, Ming Sze January 2010 (has links)
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and is characterized by progressive paralysis leading to death, typically, within 3-5 years of the onset of symptoms. The majority of ALS cases are sporadic with no known causative agent; however, 5-10% of ALS cases are genetically inherited and termed familial ALS (fALS). Approximately, 15-20% of these fALS cases have been linked to mutations in the gene encoding human Cu/Zn superoxide dismutase (hSOD). To date, over 140 hSOD mutations have been discovered. The mechanisms by which mutant hSOD confers toxicity in fALS patients are still unknown. However, there is growing evidence that ALS is a type of protein conformational disease whereby cell damage or death is caused by the accumulation of protein aggregates in the cell. It is hypothesized that mutations destabilise hSOD and increase its propensity to aggregate. There is some controversy as to which hSOD species contributes to aggregation. Many believe that only apo or mismetallated forms of hSOD are able to aggregate. Due to the abundance of fully metallated or holo hSOD in the cell, we hypothesize that holo hSOD can also lead to aggregation. Holo dimer interface mutants A4S, A4T and I113T as well as G41D were found to be destabilized compared to holo pseudo wildtype (pWT) while zinc binding mutant H80R was shown to form fragments via an unknown mechanism. Holo dimer interface mutants A4S and A4T were also shown to have an increased propensity to aggregate compared to pWT, which correlates to their decreased stability as well a short disease durations.
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Stability and aggregation propensities of ALS-associated human superoxide dismutase mutantsTong, Ming Sze January 2010 (has links)
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and is characterized by progressive paralysis leading to death, typically, within 3-5 years of the onset of symptoms. The majority of ALS cases are sporadic with no known causative agent; however, 5-10% of ALS cases are genetically inherited and termed familial ALS (fALS). Approximately, 15-20% of these fALS cases have been linked to mutations in the gene encoding human Cu/Zn superoxide dismutase (hSOD). To date, over 140 hSOD mutations have been discovered. The mechanisms by which mutant hSOD confers toxicity in fALS patients are still unknown. However, there is growing evidence that ALS is a type of protein conformational disease whereby cell damage or death is caused by the accumulation of protein aggregates in the cell. It is hypothesized that mutations destabilise hSOD and increase its propensity to aggregate. There is some controversy as to which hSOD species contributes to aggregation. Many believe that only apo or mismetallated forms of hSOD are able to aggregate. Due to the abundance of fully metallated or holo hSOD in the cell, we hypothesize that holo hSOD can also lead to aggregation. Holo dimer interface mutants A4S, A4T and I113T as well as G41D were found to be destabilized compared to holo pseudo wildtype (pWT) while zinc binding mutant H80R was shown to form fragments via an unknown mechanism. Holo dimer interface mutants A4S and A4T were also shown to have an increased propensity to aggregate compared to pWT, which correlates to their decreased stability as well a short disease durations.
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