Signaling mechanisms and cis -regulatory control of Samd14 in erythroid regeneration.

PURPOSE OF REVIEW

This review evaluates the known mechanisms of regulating erythroid regeneration via the sterile alpha motif protein-14 ( Samd14 ) enhancer, Samd14's role in stem cell factor/Kit and erythropoietin (Epo) signaling, possible SAMD14 functions beyond erythropoiesis, and extrapolation to other anemia-response pathways.

RECENT FINDINGS

Samd14 expression is controlled by an anemia-activated E-box-GATA transcriptional enhancer required for erythroid regeneration, and the Samd14 protein is needed for acute anemia recovery. Samd14 interacts with actin capping proteins to elevate Kit signaling via MAPK and PI3K/Akt pathways in stress erythroid precursors and promotes Epo signaling at later stages. Whereas canonical cellular stress transcriptional mechanisms are involved in anemia (e.g. hypoxia-inducible HSF1, Nrf2, ATF4, and others), enhancers with sequence and molecular features resembling the Samd14 S14E cis -element - occupied by GATA1 and TAL1 - regulate anemia-activated proteins. Relative to physiological replacement of red blood cells, unique signaling cues are involved in erythroid regeneration at multiple stages.

SUMMARY

Anemia-activated proteins coordinate an acute increase in red blood cell production from erythroid progenitors to regenerate lost cells and restore homeostasis. The Samd14 locus provides an exemplary examination of cell signaling - through both stem cell factor/Kit and Epo as well as transcriptional mechanisms involved in erythroid regeneration.