Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo

In most cells, transferrin receptor (TfR1)-mediated endocytosis is a major pathway for cellular iron uptake. We recently cloned the human transferrin receptor 2 (TfR2) gene, which encodes a second receptor for transferrin (Ka wabata, H., Yang, R., Hirama, T., Vuong, P, T., Kawano, S., Gombart, A. F., and Koeffler, H. P, (1999) J. Biol. Chen. 274, 20826-20832). In the presen t study, the regulation of TfR2 expression and function was investigated. A select Chinese hamster ovary (CHO)-TRVb cell line that does not express ei ther TfR1 or TfR2 was stably transfected with either TfR1 or TfR2-alpha cDN A. TfR2-alpha-expressing cells had considerably lower affinity for holotran sferrin when compared with TfR1-expressing CHO cells, Interestingly, in con trast to TfR1, expression of TfR2 mRNA in K562 cells was not up-regulated b y desferrioxamine (DFO), a cell membrane-permeable iron chelator. In MG63 c ells, expression of TfR2 mRNA if as regulated in the cell cycle with the hi ghest expression in late G(1) phase and no expression in G(0)/G(1). DFO red uced cell proliferation and DNA synthesis of CHO-TRVb control cells, wherea s it had little effect on TfR2-alpha-expressing CHO cells when measured by clonogenic and cell cycle analysis. In addition, CHO cells that express TfR 2-alpha developed into tumors in nude mice whereas CHO control cells did no t. In conclusion, TfR2 expression may be regulated by the cell cycle rather than cellular iron status and may support cell growth both in vitro and in vivo.