An investigation into the role of human mesoderm induction-early response 1 (hMI-ER1) in regulating a histone acetyltransferase, a chromatin remodeling enzyme

Blackmore, Tina M. (2004) An investigation into the role of human mesoderm induction-early response 1 (hMI-ER1) in regulating a histone acetyltransferase, a chromatin remodeling enzyme. Masters thesis, Memorial University of Newfoundland.

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Abstract

xmi-er 1, Xenopus mesoderm induction early response 1 gene, was initially discovered as a developmentally regulated gene that was transcribed in response to fibroblast growth factor (FGF). FGF family members are involved in mitogenesis, differentiation, and angiogenesis (Baird and Klagsbrun, 1991). Additional studies revealed that XMI-ER1 functioned as a potent transcriptional activator, where the N-terminalacidic domain was responsible for the activity. The human orthologue of mi-er 1, hmi-er 1, was also isolated and was shown to be 91% similar to xmi-er 1. Further analysis revealed that hmi-er 1 expression levels were upregulated in breast carcinoma cell lines and tissue, and that it acted as a transcriptional repressor by interaction with a histone deacetylase, HDAC1, through its ELM2 domain (Paterno et al., 1998; Paterno et al., 2002; Ding et al., 2003). HDACs and histone acetyltransferases (HATs) are enzymes that play a very important role in modifying histones, altering chromatin, and regulating transcription. -- In this study, we further investigated the role of hMI-ER1 in the regulation of transcription. We demonstrated that hMI-ER1B, an isoform ofhMI-ER1, inhibited the HAT activity of the coactivator Creb-binding protein (CBP). hMI-ER1β physically interacted with CBP, and the interaction led to the inhibition of CBP HAT activity. The interaction required a region within aa 1-179 ofhMI-ER1, an area containing several acidic regions. Within the CBP molecule, a region located between aa 1092-2441, which contains a bromodomain, a C/H2 and C/H3 domain, a HAT domain, and a Q rich domain, was required for the interaction. The results indicate that hMI-ER1 interacts with CBP and that it has the potential to play a role in HAT-mediated transcription.

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