Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways

Abstract

Stem cell factor (SCF) has been suggested as essential for optimal production of various hematopoietic lineages mainly because of its apoptosis prevention function when it costimulates with other cytokines. However, the underlying mechanism of this synergism of apoptosis prevention is largely unknown. The present study examined the expression of some Bcl-2 family members, including Bcl-2, Bcl-XL, Mcl-1, and Bax, in response to cytokine stimulation in TF-1 and JYTF-1 cells in which SCF costimulation is differentially required for optimal proliferation. The results revealed that only the expression of Mcl-1 highly correlated with the antiapoptotic activity of interleukin-5 (IL-5) and the synergistic effect of SCF. In TF-1 cells, the defect of IL-5 in apoptosis suppression and Mcl-1 induction was associated with the incapability to highly phosphorylate Janus kinases (JAK1, JAK2), signal transducer and activator of transcription-5 (STAT5), mitogen-activated protein kinase (MAPK), and Akt/PKB, whereas SCF costimulation restored the potent phosphorylation of MAPK and Akt/PKB, but not STAT5. The importance of MAPK and Akt/PKB signaling pathways in regulating the expression of Mcl-1 and cell survival was further supported by the observation that inhibition of MEK by PD98059 or phosphatidylinositol-3 kinase (PI-3K) by LY294002 independently resulted in the reduction of Mcl-1 expression and loss of cell viability. Therefore, the data suggest that Mcl-1 is a common antiapoptotic target of both early-stage cytokine SCF and late-stage cytokine IL-5. Both MEK/MAPK and PI-3K/Akt signaling pathways are essential in the regulation of Mcl-1 expression and apoptosis prevention.

Hepatocyte growth factor induces Mcl-1 in primary human hepatocytes and inhibits CD95-mediated apoptosis via Akt

“…The cell type‐specific mechanisms that contribute to the regulation of Mcl‐1 are controversial. Mcl‐1 expression has been described to be dependent on PI3K/Akt signaling,36 MEK/ERK signaling,35 Janus kinase/STAT signaling,46 and serine 727 ‐phosphorylated STAT3 36. In our study, inhibition of MEK/ERK signaling by PD98059 did not inhibit Mcl‐1 induction significantly on HGF treatment of PHH.…”

“…Having demonstrated that HGF induces Mcl‐1 expression in PHH, we next investigated how Mcl‐1 expression is regulated in PHH. The mechanisms contributing to regulation of Mcl‐1 expression are controversially discussed and include activation of the PI3K/Akt pathway,34 the MEK/ERK pathway,35 and the Janus kinase/STAT3 pathway,36 depending on cell type. First, we tested whether HGF also activates these pathways in PHH.…”

The life of a cell: apoptosis regulation by the PI3K/PKB pathway

“…Some specific studies have also highlighted ways in which apoptotic regulatory proteins can be specifically regulated at the translational level by PI3K/PKB. For example, we and others have shown that PI3K activity contributes to increased translation of the pro-survival Bcl-2 family protein, Mcl-1 [152,153], which had earlier been shown to be transcriptionally regulated by cytokines as well [154]. Maintenance of normal protein synthesis can also be considered an essential event in cell survival, based on the fact that ER (endoplasmic reticulum) stress resulting from blocked protein synthesis can lead to apoptosis [155,156].…”

Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1

“…A number of recent studies demonstrated the induction of the antiapoptotic BCL-2 family member MCL-1 by a number of growth factors, such as stem cell factor and IL-5 (Huang et al, 2000), IL-6 (Jourdan et al, 2003), VEGF (Le Gouill et al, 2004), GM-CSF, and IL-3 (Wang et al, 1999), as well as through B cell receptor stimulation (Petlickovski et al, 2005). While transcription seems to be a regulatory component in some cases, the exact mechanism for the maintenance of MCL-1 levels preventing MOMP has been elusive.…”