Figure 6.

Working model Hepatic BMP6, ATOH8, SMAD7 and ID1 levels are increased by increased tissue iron stores, however only ATOH8 levels are decreased by increased erythropoietic activity. ATOH8 regulates HAMP levels via direct transcriptional activation of the HAMP gene via binding to E-boxes (possibly as a heterodimer with other as yet unidentified bHLH or bHLH-ZIP proteins) and by modulation of cellular pSMAD1,5,8 levels. Reductions in hepatic ATOH8 levels under increased erythroid activity lead to reduced pSMAD1,5,8 levels and E-box dependent HAMP transcription. Dashed arrows indicate hypothetical connections between ATOH8 and other proteins. ATOH8 may be a component of signal transduction pathways linking HAMP transcription with levels of diferric transferrin (via iron-sensing molecules such as HFE and TfR2) and with erythroid activity (by as yet unidentified erythroid regulators).