Crossing paths: interactions between the cell death machinery and growth factor survival signals

Abstract

Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3 and granulocyte-macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine signalling and apoptotic pathways intersect.

JAK/STAT autocontrol of ligand-producing cell number through apoptosis

“…A role for STAT in cell death and survival has been clearly documented in mammals, and depending on which of the seven mammalian Stat genes is considered and on the cellular context, both pro-and anti-apoptotic functions have been characterised (Battle and Frank, 2002;Stephanou and Latchman, 2005;Kim and Lee, 2007;Brumatti et al, 2010). In the Drosophila developing wing, phosphorylated Stat92E has been shown to be necessary for protection against stress-induced apoptosis, but not for wing developmental apoptosis (Betz et al, 2008).…”

Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations

“…In myeloid progenitor cells, interleukin-3 (IL-3) maintains cell viability and promotes proliferation. 1 When IL-3 signalling is lost, cells activate intrinsic cell death pathways that are regulated by the Bcl-2 family of proteins. 2,3 An inappropriate repression of cell death and activation of proliferation cooperate to cause haematological malignancies, and the signalling pathways that maintain cell viability therefore stand out as important therapeutic targets in these diseases.…”

Late steps of parvoviral infection induce changes in cell morphology

“…Other survival pathways, like the PI3K/AKT pathway utilized by rotavirus [20] or pathways inhibiting apoptosis [75], are possibly having a role during CPV infection. Parvoviral NS1 protein is known for its cytotoxic nature [35,36,42,[63][64][65].…”