Participation of Signaling Cascades in the Regulation of Erythropoiesis under Conditions of Cytostatic Treatment

Abstract

We studied the role of signaling pathways in the regulation of erythropoiesis against the background of myelosuppression caused by administration of 5-fluorouracil. The important role of cyclic AMP in the maturation of erythroid progenitors after cytostatic treatment was demonstrated. The secretory activity of myelokaryocytes during the period of erythroid hemopoiesis recovery is mainly regulated via the p38 MAPK signaling pathway; non-erythropoietin factors are involved in the formation of erythropoietic activity of adherent cells of the microenvironment.

Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development

“…Deregulation of c-kit signaling is linked to cancer and allergy [7]. In hematopoietic cells, c-kit expression is detected in stem and early progenitor populations [8] and lost during differentiation in all lineages except mast and dendritic cells [3]. Activation of c-kit is initiated by dimerization of two c-kit receptors that is brought about by simultaneous binding to the two molecules of the SCF dimer [9].…”

“…Phosphorylated c-Kit receptors recruit adaptor proteins, including Grb7, Grb10, APS, Lnk, CrkI, CrkII, and CrkL, which, in turn, recruit kinases that are activated [3]. Most notable of these is the p85 subunit of PI3K [10].…”

“…The MAPK family of kinases is another large and impactful group of signaling molecules activated upon c-Kit stimulation [3]. ERK1/2 are the most characterized of these, and this pathway is initiated when the small GTPase, RAS, has the guanosine triphosphate (GDP) associated with it exchanged for a guanosine triphosphate (GTP) by a guanine exchange factor [13,14].…”

“…There are numerous MAPK family members that signal using a similar template to that of ERK1/2, including the more characterized p38, JNK, and ERK5 signals. All Stem Cell Factor (SCF) is a dimeric cytokine [6] that binds to the extracellular domain and activates the tyrosine kinase c-kit [3]. Signaling through c-kit is crucial for normal hematopoiesis and a range of other processes, including pigmentation, fertility, gut movement, and aspects of the nervous system [3].…”

“…Aberrant kinase activation contributes to the pathogenesis of many diseases, including hematopoietic disorders, and pharmacologic inhibition of these kinases has become a major therapeutic strategy in the management of these diseases [1][2][3][4][5][6]. Indeed, the first protein-targeting therapy (imatinib mesylate, sti-571, or Geevec ® ) was designed to inhibit the kinase activity of the fusion gene Bcr-Abl in chronic Myeloid Leukemia [7].…”