The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels.
Bottom Line: ATOH8 expression in HEK293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity.Mutation of the E-box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH8, indicating that ATOH8 activates HAMP transcription directly as well as through bone morphogenic protein (BMP) signalling.Liver Atoh8 levels were reduced in mice under conditions associated with increased erythropoietic activity such as hypoxia, haemolytic anaemia, hypotransferrinaemia and erythropoietin treatment and increased by inhibitors of erythropoiesis.
Affiliation: Division of Diabetes and Nutritional Sciences, Kings College London, London, UK.Show MeSH
Related in: MedlinePlus
Mentions: Transferrin saturation correlates directly with erythropoietic activity (Frazer et al, 2004) while numerous studies in vivo show that serum diferric transferrin levels correlate with liver Hamp1 levels in mice (Wilkins et al, 2006; Bartnikas et al, 2010; Li et al, 2010; Ramos et al, 2011). It is thought that increased diferric transferrin levels leads to stabilization of TfR2, possibly due to binding of Hfe (Robb & Wessling-Resnick, 2004; Schmidt et al, 2008), generating an as yet unidentified signal leading to increased HAMP levels. Our data, showing that that holo-transferrin also directly regulates liver Atoh8 levels, suggest that this signalling pathway may involve ATOH8 (Fig6). However ATOH8 levels were also suppressed in Hamp1−/− mice after PHZ treatment where plasma iron remains high in the former (Masaratana et al, 2012) Thus it is possible that other as yet unidentified erythroid factor (s) released from rapidly developing erythrocytes or the bone marrow also regulate Atoh8 levels (Fig6). Interestingly, hepatic Atoh8 levels were not increased in Hfe knockout mice, in contrast to other iron loaded models (Kautz et al, 2008, 2009). This indicates that HFE may also be required for regulation of ATOH8. Further work is required to uncover the link between iron sensing molecules and ATOH8.
Affiliation: Division of Diabetes and Nutritional Sciences, Kings College London, London, UK.