Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo

Shaina L. Byrne, Peter D. Buckett, Jonghan Kim, Flora Luo, Jack Sanford, Juxing Chen, Caroline Enns, Marianne Wessling-Resnick

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Previous studies have shown that the small molecule iron transport inhibitor ferristatin (NSC30611) acts by down-regulating transferrin receptor-1 (TfR1) via receptor degradation. In this investigation, we show that another small molecule, ferristatin II (NSC8679), acts in a similar manner to degrade the receptor through a nystatin-sensitive lipid raft pathway. Structural domains of the receptor necessary for interactions with the clathrin pathway do not appear to be necessary for ferristatin II induced degradation of TfR1. While TfR1 constitutively traffics through clathrin-mediated endocytosis, with or without ligand, the presence of Tf blocked ferristatin II induced degradation of TfR1. This effect of Tf was lost in a ligand binding receptor mutant G647A TfR1, suggesting that Tf binding to its receptor interferes with the drug's activity. Rats treated with ferristatin II have lower TfR1 in liver. These effects are associated with reduced intestinal 59Fe uptake, lower serum iron and transferrin saturation, but no change in liver non-heme iron stores. The observed hypoferremia promoted by degradation of TfR1 by ferristatin II appears to be due to induced hepcidin gene expression.

Original languageEnglish (US)
Article numbere70199
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 23 2013

Fingerprint

Transferrin Receptors
transferrin
Degradation
receptors
degradation
Clathrin
ferristatin
Iron
Liver
clathrin
Hepcidins
Ligands
Nystatin
iron
Molecules
Transferrin
Endocytosis
ferristatin II
In Vitro Techniques
Gene expression

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Byrne, S. L., Buckett, P. D., Kim, J., Luo, F., Sanford, J., Chen, J., ... Wessling-Resnick, M. (2013). Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo. PLoS One, 8(7), [e70199]. https://doi.org/10.1371/journal.pone.0070199

Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo. / Byrne, Shaina L.; Buckett, Peter D.; Kim, Jonghan; Luo, Flora; Sanford, Jack; Chen, Juxing; Enns, Caroline; Wessling-Resnick, Marianne.

In: PLoS One, Vol. 8, No. 7, e70199, 23.07.2013.

Research output: Contribution to journalArticle

Byrne, SL, Buckett, PD, Kim, J, Luo, F, Sanford, J, Chen, J, Enns, C & Wessling-Resnick, M 2013, 'Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo', PLoS One, vol. 8, no. 7, e70199. https://doi.org/10.1371/journal.pone.0070199
Byrne SL, Buckett PD, Kim J, Luo F, Sanford J, Chen J et al. Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo. PLoS One. 2013 Jul 23;8(7). e70199. https://doi.org/10.1371/journal.pone.0070199
Byrne, Shaina L. ; Buckett, Peter D. ; Kim, Jonghan ; Luo, Flora ; Sanford, Jack ; Chen, Juxing ; Enns, Caroline ; Wessling-Resnick, Marianne. / Ferristatin II Promotes Degradation of Transferrin Receptor-1 In Vitro and In Vivo. In: PLoS One. 2013 ; Vol. 8, No. 7.
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