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Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to the proliferative Ras/RAF and the nutrient-dependent mTOR signaling pathways

Abstract:

The hepatic hormone hepcidin is a key regulator of systemic iron metabolism. Its expression is largely regulated by two signaling pathways, the 'iron-regulated' bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways. To obtain broader insights into cellular processes that modulate hepcidin transcription and to provide a resource to identify novel genetic modifiers of systemic iron homeostasis we designed an RNAi screen that monitors hepcidin promoter activity following the knock-down of 19 599 genes in hepatocarcinoma cells. Interestingly, many of the putative hepcidin activators play roles in signal transduction, inflammation or transcription and affect hepcidin transcription through BMP-responsive elements. Furthermore, our work sheds light on new components of the transcriptional machinery that maintain steady-state levels of hepcidin expression and its responses to the BMP- and IL-6-triggered signals. Notably, we discover hepcidin suppression mediated via components of Ras/RAF MAPK and mTOR signaling, linking hepcidin transcriptional control to the pathways that respond to mitogen stimulation and nutrient status. Thus, using a combination of RNAi screening, reverse phase protein arrays and small molecules testing, we identify links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis as well as nutrient metabolism.

24385536

Projects: A3.4: Linking signalling to metabolic functions, B1.3: Linking modulation of iron metabolism with the impact of macrophag...

Blood
Blood :
5th Jan 2014

Katarzyna Mleczko-Sanecka, Franziska Roche, Ana Rita da Silva, Debora Call, Flavia D'Alessio, Anan Ragab, Philip E Lapinski, Ramesh Ummanni, Ulrike Korf, Christopher Oakes, Georg Damm, Lorenza A D'Alessandro, Ursula Klingmüeller, Philip D King, Michael Boutros, Matthias W Hentze, Martina U Muckenthaler

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[Georg Damm] [Lorenza D'Alessandro] [Matthias Hentze] [Martina Muckenthaler]

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Cell and Intercellular
Views: 1561
  • Created: 14th Jan 2014 at 12:06

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