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- W73228081 abstract "Erythropoiesis is regulated through a long-range negative feedback loop, whereby tissue hypoxia stimulates erythropoietin (Epo) secretion, which promotes an increase in erythropoietic rate. However, this long-range feedback loop, by itself, cannot account for the observed system properties of erythropoiesis, namely, a wide dynamic range, stability in the face of random perturbations, and a rapid stress response. Here, we show that three Epo-regulated erythroblast survival pathways each give rise to distinct system properties. The induction of Bcl-xL by signal transducer and activator of transcription 5 (Stat5) is responsive to the rate of change in Epo levels, rather than to its absolute level, and is therefore maximally but transiently activated in acute stress. By contrast, Epo-mediated suppression of the pro-survival Fas and Bim pathways is proportional to the levels of stress/Epo and persists throughout chronic stress. Together, these elements operate in a manner reminiscent of a “proportional-integral-derivative (PID)” feedback controller frequently found in engineering applications. A short-range negative autoregulatory loop within the early erythroblast compartment, operated by Fas/FasL, filters out random noise and controls a reserve pool of early erythroblasts that is poised to accelerate the response to acute stress. Both these properties have previously been identified as inherent to negative regulatory motifs. Finally, we show that signal transduction by Stat5 combines binary and graded modalities, thereby increasing signaling fidelity over the wide dynamic range of Epo found in health and disease." @default.
- W73228081 created "2016-06-24" @default.
- W73228081 creator A5051245436 @default.
- W73228081 creator A5074644339 @default.
- W73228081 creator A5091020237 @default.
- W73228081 creator A5091857498 @default.
- W73228081 date "2014-01-01" @default.
- W73228081 modified "2023-10-16" @default.
- W73228081 title "Erythropoiesis: From Molecular Pathways to System Properties" @default.
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- W73228081 doi "https://doi.org/10.1007/978-1-4939-2095-2_3" @default.
- W73228081 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25480636" @default.
- W73228081 hasPublicationYear "2014" @default.
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