Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression.
Reactive oxygen species are involved in many cellular metabolic and signalling processes and are thought to have a role in disease, particularly in carcinogenesis and ageing. We have generated mice with targeted inactivation of Prdx1, a member of the peroxiredoxin family of antioxidant enzymes. 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.
Neumann
Carola A
CA
Center for Blood Research and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Krause
Daniela S
DS
Carman
Christopher V
CV
Das
Shampa
S
Dubey
Devendra P
DP
Abraham
Jennifer L
JL
Bronson
Roderick T
RT
Fujiwara
Yuko
Y
Orkin
Stuart H
SH
Van Etten
Richard A
RA
D000375:Aging / Q000378:metabolism; D000743:Anemia, Hemolytic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002453:Cell Cycle; D002470:Cell Survival; D004249:DNA Damage; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006151:Guanosine / Q000031:analogs & derivatives* / Q000032:analysis; D006454:Hemoglobins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008136:Longevity / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010544:Peroxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
D000975:Antioxidants; D006454:Hemoglobins; D017382:Reactive Oxygen Species; D006151:Guanosine; C046215:8-hydroxyguanosine; D010544:Peroxidases; D054464:Peroxiredoxins