Abstract
Human heavy-chain (H-) ferritin muteins obtained by oligonucleotide site-directed mutagenesis, together with wild-type recombinant human H- and light-chain (L-) ferritins, were evaluated for in vitro effects on the suppression of human bone marrow myeloid progenitor cells and for in vivo effects on marrow and splenic myelopoiesis in C3H/HeJ mice. The 10 H-ferritin muteins exhibited alterations of various regions of the molecule, including ones exposed on the outer surface, on the inner cavity, and on the hydrophilic and hydrophobic channels and of the four-α-helix bundle forming the subunit structure. They were stable and were electrophoretically analogous to wild-type H-ferritin. The muteins showed in vitro and in vivo myelosuppressive activity analogous to wild type, except for mutein 222, which was totally inactive and which lacked ferroxidase activity. Recombinant human L-ferritin, devoid of ferroxidase activity, was also inactive as a suppressor. The results demonstrate that H-ferritin myelosuppressive and ferroxidase activities are linked. One possibility is that ferroxidase activity may interfere with the cellular uptake of transferrin iron that is needed for cell proliferation, an interpretation consistent with the presently described ability of hemin to overcome H-ferritin suppressive effects.
| Original language | English |
|---|---|
| Pages (from-to) | 770-774 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 88 |
| Issue number | 3 |
| State | Published - 1991 |
Fingerprint
ASJC Scopus subject areas
- General
- Genetics
Cite this
Mutated recombinant human heavy-chain ferritins and myelosuppression in vitro and in vivo : A link between ferritin ferroxidase activity and biological function. / Broxmeyer, Hal; Cooper, Scott; Levi, Sonia; Arosio, Paolo.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, No. 3, 1991, p. 770-774.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutated recombinant human heavy-chain ferritins and myelosuppression in vitro and in vivo
T2 - A link between ferritin ferroxidase activity and biological function
AU - Broxmeyer, Hal
AU - Cooper, Scott
AU - Levi, Sonia
AU - Arosio, Paolo
PY - 1991
Y1 - 1991
N2 - Human heavy-chain (H-) ferritin muteins obtained by oligonucleotide site-directed mutagenesis, together with wild-type recombinant human H- and light-chain (L-) ferritins, were evaluated for in vitro effects on the suppression of human bone marrow myeloid progenitor cells and for in vivo effects on marrow and splenic myelopoiesis in C3H/HeJ mice. The 10 H-ferritin muteins exhibited alterations of various regions of the molecule, including ones exposed on the outer surface, on the inner cavity, and on the hydrophilic and hydrophobic channels and of the four-α-helix bundle forming the subunit structure. They were stable and were electrophoretically analogous to wild-type H-ferritin. The muteins showed in vitro and in vivo myelosuppressive activity analogous to wild type, except for mutein 222, which was totally inactive and which lacked ferroxidase activity. Recombinant human L-ferritin, devoid of ferroxidase activity, was also inactive as a suppressor. The results demonstrate that H-ferritin myelosuppressive and ferroxidase activities are linked. One possibility is that ferroxidase activity may interfere with the cellular uptake of transferrin iron that is needed for cell proliferation, an interpretation consistent with the presently described ability of hemin to overcome H-ferritin suppressive effects.
AB - Human heavy-chain (H-) ferritin muteins obtained by oligonucleotide site-directed mutagenesis, together with wild-type recombinant human H- and light-chain (L-) ferritins, were evaluated for in vitro effects on the suppression of human bone marrow myeloid progenitor cells and for in vivo effects on marrow and splenic myelopoiesis in C3H/HeJ mice. The 10 H-ferritin muteins exhibited alterations of various regions of the molecule, including ones exposed on the outer surface, on the inner cavity, and on the hydrophilic and hydrophobic channels and of the four-α-helix bundle forming the subunit structure. They were stable and were electrophoretically analogous to wild-type H-ferritin. The muteins showed in vitro and in vivo myelosuppressive activity analogous to wild type, except for mutein 222, which was totally inactive and which lacked ferroxidase activity. Recombinant human L-ferritin, devoid of ferroxidase activity, was also inactive as a suppressor. The results demonstrate that H-ferritin myelosuppressive and ferroxidase activities are linked. One possibility is that ferroxidase activity may interfere with the cellular uptake of transferrin iron that is needed for cell proliferation, an interpretation consistent with the presently described ability of hemin to overcome H-ferritin suppressive effects.
UR - http://www.scopus.com/inward/record.url?scp=0026013466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026013466&partnerID=8YFLogxK
M3 - Article
C2 - 1992468
AN - SCOPUS:0026013466
VL - 88
SP - 770
EP - 774
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 3
ER -