ABSTRACT
Abcb10, member 10 of the ABC transporter family, is reportedly a part of a complex in the mitochondrial inner membrane with mitoferrin-1 (Slc25a37) and ferrochelatase (Fech) and is responsible for heme biosynthesis in utero. However, it is unclear whether loss of Abcb10 causes pathological changes in adult mice. Here, we show that Abcb10(-/-) mice lack heme biosynthesis and erythropoiesis abilities and die in midgestation. Moreover, we generated Abcb10(F/-); Mx1-Cre mice, with Abcb10 in hematopoietic cells deleted, which showed accumulation of protoporphyrin IX and maturation arrest in reticulocytes. Electron microscopy images of Abcb10(-/-) hematopoietic cells showed a marked increase of iron deposits at the mitochondria. These results suggest a critical role for Abcb10 in heme biosynthesis and provide new insights into the pathogenesis of erythropoietic protoporphyria and sideroblastic anemia.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Anemia/genetics , Heme/genetics , Iron/metabolism , Protoporphyrins/metabolism , ATP-Binding Cassette Transporters/metabolism , Anemia/metabolism , Animals , Erythroid Cells/metabolism , Erythropoiesis/genetics , Heme/metabolism , Mice , Mice, Inbred C57BL , Mitochondria/genetics , Mitochondria/metabolism , Protoporphyrins/genetics , Reticulocytes/metabolismABSTRACT
Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours.
