Hydroxyurea-inducible SAR1 gene acts through the Giα/JNK/Jun pathway to regulate γ-globin expression

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NIDDK	DIR-15

* FARE Award Winner

Authors

• J Zhu
• K Chin
• W Aerbajinai
• C Kumkhaek
• H Li
• G.P. Rodgers

Abstract

Hydroxyurea (HU) has been effectively used in the treatment of β-hemoglobinopathies by augmenting the production of fetal hemoglobin (HbF, α2γ2). The molecular mechanisms underlying HU-mediated γ-globin induction remain to be fully defined. The HU-induced Secretion-associated and ras-related protein (SAR1), a small guanosine triphosphate (GTP)-binding protein which functions in protein transport form ER to Golgi, closely mimics the known effects of HU on erythroid cells. We previously reported that over-expression of the SAR1 gene increased γ-globin expression in K562 and CD34+ cells, and SAR1 is an obligatory mediator to the effect of HU in HbF induction, cell-cycle regulation and apoptosis. Here we report of our further investigation on which regulatory elements in the SAR1 gene promoter region and its cognate DNA-binding proteins that confer HU inducibility on SAR1 expression, and what signal transduction pathway(s) participates in SAR1-mediated HbF induction. The further exploration of the mechanistic details underlying SAR1 effects in erytroid cells may provide an alternative therapeutic target for β-globin disorders.

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