Regulation of Trib2 gene expression in normal and AML cells

Hannon, M., Al-Shahrour, F., Ebert, B. L. and Keeshan, K. (2011) Regulation of Trib2 gene expression in normal and AML cells. British Journal of Haematology, 153(Supl 1), pp. 6-7. (doi: 10.1111/j.1365-2141.2011.08609.x)

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The mammalian Trib family consists of Trib1, Trib2 and Trib3.Elevated levels of Trib2 have been linked with murine AML andassociates with a specific subset of human AML with Notch1mutations and dysregulated C/EBPa. However the regulation of Tribexpression is poorly understood; understanding this regulation isimportant both physiologically and pathologically.Promoter analyses indicated that several possible E2F1 bindingsites exist within the Trib2 promoter region. A complex regulatoryrelationship exists between C/EBPa and E2F1, and proliferationarrest mediated by C/EBPa involves repression of E2F1-target genes.Luciferase assays using a Trib2 promoter construct demonstratedthat E2F1 is a positive regulator of Trib2 and that this positiveinduction was dependent on E2F1’s ability to bind directly to DNA.Further analyses revealed that this activation is repressed by wild type C/EBPa. Importantly, C/EBPap30, an N-terminal truncateddominant negative C/EBPa isoform commonly associated with AMLco-operated with E2F1 to induce Trib2 promoter activity. Bioinfor-matic analysis of human AML datasets revealed a negativecorrelation between Trib2 and C/EBPa expression, and a positivecorrelation between Trib2 and Notch1 expression. These resultscorrespond with our previous findings that Trib2 is a Notch1 targetgene and functions to degrade and inhibit wild type C/EBPa. Furtheranalyses demonstrated a positive correlation between Trib2 and E2F1expression in the human AML dataset supporting our findings.Together these data indicate a positive regulatory pathway forTrib2 expression mediated by E2F1 and C/EBPap30, and a negativeregulatory pathway involving E2F1 and wild type C/EBPa.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen
Authors: Hannon, M., Al-Shahrour, F., Ebert, B. L., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Haematology
Publisher:Blackwell Publishing

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