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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.

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

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Effect of Hypoxia, EPO, Carboplatin and Transferrin on liver Atoh8 mRNA levels. (A) qPCR shows relative Atoh8 levels (normalized to Rpl19; plotted fold-change relative to control). Control (saline-injected; n = 7), EPO (n = 4), carboplatin (CARB; n = 4) and EPO and Carboplatin injected mice (EPO + CARB; n = 4). (B) serum iron levels in treated mice. (C) Correlation between serum iron and Atoh8mRNA in all mice (Pearson correlation coefficient, R2 = 0·70, P = 0·013, n = 19). (D) qPCR of liver Atoh8mRNA levels in control (normoxia) and in mice exposed to hypoxia for 24 and 72 h (Atoh8 levels normalized to Rpl19, plotted as fold-change relative to control) (E) Atoh8 levels in control (saline injected) (n = 7), Holo-transferrin (n = 4) or Apo-transferrin (n = 4) (Atoh8 levels normalized to Rpl19; plotted as fold-change relative to control) (F) serum iron levels in treated mice. Data are presented as mean ± SD. Statistical comparisons were made using 1-way anova with Tukey's post hoc test.
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fig05: Effect of Hypoxia, EPO, Carboplatin and Transferrin on liver Atoh8 mRNA levels. (A) qPCR shows relative Atoh8 levels (normalized to Rpl19; plotted fold-change relative to control). Control (saline-injected; n = 7), EPO (n = 4), carboplatin (CARB; n = 4) and EPO and Carboplatin injected mice (EPO + CARB; n = 4). (B) serum iron levels in treated mice. (C) Correlation between serum iron and Atoh8mRNA in all mice (Pearson correlation coefficient, R2 = 0·70, P = 0·013, n = 19). (D) qPCR of liver Atoh8mRNA levels in control (normoxia) and in mice exposed to hypoxia for 24 and 72 h (Atoh8 levels normalized to Rpl19, plotted as fold-change relative to control) (E) Atoh8 levels in control (saline injected) (n = 7), Holo-transferrin (n = 4) or Apo-transferrin (n = 4) (Atoh8 levels normalized to Rpl19; plotted as fold-change relative to control) (F) serum iron levels in treated mice. Data are presented as mean ± SD. Statistical comparisons were made using 1-way anova with Tukey's post hoc test.

Mentions: Given that PHZ injection results in other effects, such as release of haem and increased oxidative stress, we investigated the effects of other more physiological modulators of erythropoiesis, such as exposure of mice to hypoxia and EPO injection on liver Atoh8 levels. In mice, EPO injection and exposure to hypoxia lead to increased erythropoiesis and suppression of liver Hamp1 mRNA (Nicolas et al, 2002a; Pak et al, 2006). On the other hand, injection of the cytotoxic agent carboplatin, which inhibits erythropoiesis, results in increased liver Hamp1 (Pak et al, 2006; Bartnikas et al, 2010). As previously shown, we found that liver Hamp1 mRNA was suppressed by EPO treatment and increased by carboplatin treatment (Fig S2A). EPO treatment significantly reduced liver Atoh8 mRNA levels by around twofold compared to control mice (P = 0·01), whereas mice treated with carboplatin alone or EPO and carboplatin had significantly higher Atoh8 mRNA levels (P < 0·01) compared to control or EPO-treated mice (Fig5A). Mice treated with carboplatin alone showed the highest induction of Atoh8 mRNA levels (approximately fourfold induction, P < 0·001).


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)

Effect of Hypoxia, EPO, Carboplatin and Transferrin on liver Atoh8 mRNA levels. (A) qPCR shows relative Atoh8 levels (normalized to Rpl19; plotted fold-change relative to control). Control (saline-injected; n = 7), EPO (n = 4), carboplatin (CARB; n = 4) and EPO and Carboplatin injected mice (EPO + CARB; n = 4). (B) serum iron levels in treated mice. (C) Correlation between serum iron and Atoh8mRNA in all mice (Pearson correlation coefficient, R2 = 0·70, P = 0·013, n = 19). (D) qPCR of liver Atoh8mRNA levels in control (normoxia) and in mice exposed to hypoxia for 24 and 72 h (Atoh8 levels normalized to Rpl19, plotted as fold-change relative to control) (E) Atoh8 levels in control (saline injected) (n = 7), Holo-transferrin (n = 4) or Apo-transferrin (n = 4) (Atoh8 levels normalized to Rpl19; plotted as fold-change relative to control) (F) serum iron levels in treated mice. Data are presented as mean ± SD. Statistical comparisons were made using 1-way anova with Tukey's post hoc test.
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fig05: Effect of Hypoxia, EPO, Carboplatin and Transferrin on liver Atoh8 mRNA levels. (A) qPCR shows relative Atoh8 levels (normalized to Rpl19; plotted fold-change relative to control). Control (saline-injected; n = 7), EPO (n = 4), carboplatin (CARB; n = 4) and EPO and Carboplatin injected mice (EPO + CARB; n = 4). (B) serum iron levels in treated mice. (C) Correlation between serum iron and Atoh8mRNA in all mice (Pearson correlation coefficient, R2 = 0·70, P = 0·013, n = 19). (D) qPCR of liver Atoh8mRNA levels in control (normoxia) and in mice exposed to hypoxia for 24 and 72 h (Atoh8 levels normalized to Rpl19, plotted as fold-change relative to control) (E) Atoh8 levels in control (saline injected) (n = 7), Holo-transferrin (n = 4) or Apo-transferrin (n = 4) (Atoh8 levels normalized to Rpl19; plotted as fold-change relative to control) (F) serum iron levels in treated mice. Data are presented as mean ± SD. Statistical comparisons were made using 1-way anova with Tukey's post hoc test.
Mentions: Given that PHZ injection results in other effects, such as release of haem and increased oxidative stress, we investigated the effects of other more physiological modulators of erythropoiesis, such as exposure of mice to hypoxia and EPO injection on liver Atoh8 levels. In mice, EPO injection and exposure to hypoxia lead to increased erythropoiesis and suppression of liver Hamp1 mRNA (Nicolas et al, 2002a; Pak et al, 2006). On the other hand, injection of the cytotoxic agent carboplatin, which inhibits erythropoiesis, results in increased liver Hamp1 (Pak et al, 2006; Bartnikas et al, 2010). As previously shown, we found that liver Hamp1 mRNA was suppressed by EPO treatment and increased by carboplatin treatment (Fig S2A). EPO treatment significantly reduced liver Atoh8 mRNA levels by around twofold compared to control mice (P = 0·01), whereas mice treated with carboplatin alone or EPO and carboplatin had significantly higher Atoh8 mRNA levels (P < 0·01) compared to control or EPO-treated mice (Fig5A). Mice treated with carboplatin alone showed the highest induction of Atoh8 mRNA levels (approximately fourfold induction, P < 0·001).

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