The Antiapoptotic Gene mcl-1 Is Up-Regulated by the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway through a Transcription Factor Complex Containing CREB

Abstract

mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) signaling pathways and plays an important role in the viability response of these cytokines. In this study, we demonstrated that cytokine stimulation of mcl-1 mRNA and protein expression were attenuated by pretreatment of cells with phosphatidylinositol 3-kinase (PI3-K) inhibitors. Reporter gene assays further showed that the PI3-K/Akt signaling pathway was involved in IL-3 activation of mcl-1 gene transcription. Analysis of the mcl-1 promoter revealed that both promoter elements, SIE at position ؊87 and CRE-2 at ؊70, contribute to IL-3 stimulation of mcl-1 gene expression. Although either the SIE site or the CRE-2 site alone was sufficient to confer IL-3 inducibility on a heterologous promoter, only IL-3 activation of the CRE-2 reporter was mediated via the PI3-K/Akt pathway. The SIE binding activity was constitutively high in cells deprived of or stimulated by IL-3. In contrast, the CRE-2 binding activity was low in cytokine-starved cells and was strongly induced within 1 h following cytokine treatment of cells. In addition, cytokine induction of the CRE-2 but not of the SIE binding activity was dependent on activation of the PI3-K/Akt signaling pathway. Lastly, we showed that CREB was one component of the CRE-2 binding complex and played a role in IL-3 activation of the mcl-1 reporter gene. Taken together, our results suggest that both PI3-K/Aktdependent and -independent pathways contribute to the IL-3 activation of mcl-1 gene expression. Activation of mcl-1 by the PI3-K/Akt-dependent pathway is through a transcription factor complex containing CREB.

Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes

“…However, Mcl-1 can act as a survival factor in hematopoeitic cells in cell culture as well as in transgenic mice (47). Furthermore, Mcl-1 may play an essential role in cytokine mediated survival of hematopoeitic cells and function as an early response gene when stimulated with granulocyte/ macrophage colony stimulating factor, (48)(49)(50). Our findings are consistent with these observations and suggest that Mcl-1 can act as an IL-6 early response gene in mediating survival signaling in malignant cholangiocytes.…”

“…Of these, inhibitor studies have identified the PI3-kinase and the p38 MAPK pathway as being involved in cell survival signaling in cholangiocytes. IL-6 induced PI 3 kinase signaling resulting in activation of Mcl-1 have been reported in several different settings (39,41,49,51). In contrast, the role of p38 MAPK in mediating Mcl-1 expression has not previously been reported to the best of our knowledge.…”

Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway

“…Our data support the fact that Mcl-1 is an inducible, antiapoptotic protein, as previously described in myeloid cells induced by TPA and GM-CSF (Kozopas et al, 1993;Chao et al, 1998), and in EBV immortalized B cells induced by IL-6 (Altmeyer et al, 1997). While the induction of Mcl-1 by TPA was mediated through the MAP kinase pathway in myeloblastic leukemia cells (Townsend et al, 1998), the IL-3 activation of mcl-1 gene expression was mediated via PI3-K-Akt-dependent andindependent pathways in murine pro-B Ba/F3 cells (Wang et al, 1999). Thus, there seems to be more than one pathway involved in the induction of Mcl-1.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…[84][85][86][87] Many of the effects of the PI3K/PTEN/Akt/mTOR pathway on apoptosis are mediated by Akt phosphorylation of important apoptotic effecter molecules (for example, Bcl-2, Mcl-1, BAD, Bim, Foxo, caspase-9 and many others). 88,89 PTEN can also regulate CREB activity, which can alter its ability to regulate the transcription of certain genes. 90 This has been shown to regulate chemotherapeutic drug sensitivity.…”