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.

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.

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.