Regulation of human 5-aminolevulinate synthase 2 expression during erythroid differentiation and its role in x-linked sideroblastic anaemia.
type: CreativeWork
description: Haem is required for many cellular processes including haemoglobin synthesis in erythroid cells, where the majority of the haem in the body is produced and utilised. Its synthesis requires tight regulation to prevent toxic levels of free haem from arising. 5-Aminolevulinate synthase 2 (ALAS2) is the first and rate limiting enzyme in the biosynthesis of haem in erythroid cells. Thus, the regulation of ALAS2 expression is critical for maintaining and controlling haem production during the process of erythroid cell differentiation. A major aim of this study was to identify the regulatory elements within the ALAS2 gene that are involved in controlling transcription of ALAS2 during erythropoietin (Epo) stimulated erythroid differentiation. In order to investigate the regulation of ALAS2 transcription in the context of red blood cell maturation, an erythroid cell line, J2E, that terminally differentiates in response to Epo treatment was employed in this study. Human ALAS2 promoter deletion studies demonstrated that the first 293bp of the proximal promoter was sufficient to enhance transcription in response to Epo induced differentiation of the J2E cells. Introns 1 and 8 exhibited Epo responsive enhancer activity with intron 8 proving to be the stronger transcriptional activator in response to Epo. Transcription factor binding sites located in the 3' end of intron 8 that are critical to intron 8 Epo responsive enhancer activity were also identified. Preliminary studies on the effect of the coactivators CREB binding protein (CBP) and p300 on ALAS2 expression in response to Epo stimulation were conducted and suggested a potential involvement of these factors in regulating ALAS2 transcription. Defective haem synthesis, as a result of point mutations in the human ALAS2 gene, has been implicated in a blood disorder called X-linked sideroblastic anaemia (XLSA). XLSA is characterised by the presence of iron loaded mitochondria surrounding the nucleus in erythroblasts of the bone …
abstract: Haem is required for many cellular processes including haemoglobin synthesis in erythroid cells, where the majority of the haem in the body is produced and utilised. Its synthesis requires tight regulation to prevent toxic levels of free haem from arising. 5-Aminolevulinate synthase 2 (ALAS2) is the first and rate limiting enzyme in the biosynthesis of haem in erythroid cells. Thus, the regulation of ALAS2 expression is critical for maintaining and controlling haem production during the process of erythroid cell differentiation. A major aim of this study was to identify the regulatory elements within the ALAS2 gene that are involved in controlling transcription of ALAS2 during erythropoietin (Epo) stimulated erythroid differentiation. In order to investigate the regulation of ALAS2 transcription in the context of red blood cell maturation, an erythroid cell line, J2E, that terminally differentiates in response to Epo treatment was employed in this study. Human ALAS2 promoter deletion studies demonstrated that the first 293bp of the proximal promoter was sufficient to enhance transcription in response to Epo induced differentiation of the J2E cells. Introns 1 and 8 exhibited Epo responsive enhancer activity with intron 8 proving to be the stronger transcriptional activator in response to Epo. Transcription factor binding sites located in the 3' end of intron 8 that are critical to intron 8 Epo responsive enhancer activity were also identified. Preliminary studies on the effect of the coactivators CREB binding protein (CBP) and p300 on ALAS2 expression in response to Epo stimulation were conducted and suggested a potential involvement of these factors in regulating ALAS2 transcription. Defective haem synthesis, as a result of point mutations in the human ALAS2 gene, has been implicated in a blood disorder called X-linked sideroblastic anaemia (XLSA). XLSA is characterised by the presence of iron loaded mitochondria surrounding the nucleus in erythroblasts of the bone …
author: Dell'Oso, Tania
keywords: human 5-aminolevulinate synthase 2 expression; x-linked siderblastic anaemia
date published: 2003
date modified: 2026-07-24T00:51:05Z
provider: University of Adelaide
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Adelaide

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property ID: Handle
value: http://hdl.handle.net/2440/92536