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The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels.

Patel N, Varghese J, Masaratana P, Latunde-Dada GO, Jacob M, Simpson RJ, McKie AT - Br. J. Haematol. (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes and Nutritional Sciences, Kings College London, London, UK.

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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).
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fig06: 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).

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.


The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels.

Patel N, Varghese J, Masaratana P, Latunde-Dada GO, Jacob M, Simpson RJ, McKie AT - Br. J. Haematol. (2013)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232863&req=5

fig06: 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).
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes and Nutritional Sciences, Kings College London, London, UK.

Show MeSH
Related in: MedlinePlus