Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression

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Abstract

Reactive oxygen species are involved in many cellular metabolic and signalling processes1 and are thought to have a role in disease, particularly in carcinogenesis and ageing2. We have generated mice with targeted inactivation of Prdx1, a member of the peroxiredoxin family of antioxidant enzymes3. Here we show that mice lacking Prdx1 are viable and fertile but have a shortened lifespan owing to the development beginning at about 9 months of severe haemolytic anaemia and several malignant cancers, both of which are also observed at increased frequency in heterozygotes. The haemolytic anaemia is characterized by an increase in erythrocyte reactive oxygen species, leading to protein oxidation, haemoglobin instability, Heinz body formation and decreased erythrocyte lifespan. The malignancies include lymphomas, sarcomas and carcinomas, and are frequently associated with loss of Prdx1 expression in heterozygotes, which suggests that this protein functions as a tumour suppressor. Prdx1-deficient fibroblasts show decreased proliferation and increased sensitivity to oxidative DNA damage, whereas Prdx1-null mice have abnormalities in numbers, phenotype and function of natural killer cells. Our results implicate Prdx1 as an important defence against oxidants in ageing mice.

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Figure 1: Premature death in ageing Prdx1-/- mice.
Figure 2: Haemolytic anaemia caused by intra-erythrocytic oxidative damage in Prdx1 mutant mice.
Figure 3: Prdx1 mutant mice are predisposed to cancer.

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Acknowledgements

We thank C. Westphal, P. Leder, K. Smith, J. Alverez, J. Pinkas and C. Brugnara for assistance, and H. F. Bunn for discussions. This work was supported by NIH grants to C.A.N., S.D., D.P.D. and R.A.V.

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Correspondence to Richard A. Van Etten.

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Neumann, C., Krause, D., Carman, C. et al. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 424, 561–565 (2003) doi:10.1038/nature01819

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