A general scheme of hematopoietic growth factor physiology. A number of modes of cytokine regulation have been identified, and include oxygen tension (acting via hypoxia inducible factor [HIF1; A] on EPO production), inflammatory mediators (acting on G-CSF and TPO production [B]) and blood cell constituents (enhancing TPO production [C]). Once these mediators bind to their corresponding cell surface receptors, or affect intracellular signaling (such as a prolyl hydroxylase [D]), signal transduction mechanisms ultimately result in enhanced growth factor gene transcription (D,E,F), mRNA translation (G,H) and protein secretion (I). Growth factors then act locally (TPO, G-CSF) or at a distance (EPO, G-CSF, TPO) by binding to their receptors on hematopoietic stem and progenitor cells (J), transducing signals that require immediate activation of a receptor-tethered kinase (K) and downstream mediators (L) including phosphoinositol-3-kianse (PI3K) and mitogen activated protein kinase (MAPK), which then alter transcription factors that affect cell survival, proliferation, differentiation or activation (M).