Cyclic nucleotide response element binding (CREB) protein activation is involved in K562 erythroleukemia cells differentiation

Abstract

K562 are human erythroleukemia cells inducible to differentiate into megakaryocytic or erythroid lineage by different agents. Cyclic nucleotide Response Element Binding (CREB) protein, a nuclear transcription factor which mediates c-AMP signaling, is a potential candidate involved in the occurrence of erythroid differentiation and adaptive response. Here we investigated signaling events in K562 cells induced with 30 microM hemin to undergo erythroid differentiation. CREB activation was detected early 1 h after hemin treatment and up to 4 and 6 days of treatment, when K562 terminal differentiation occurs together with caspase-3 maximal activation and PARP degradation. It was interesting to note that after hemin treatment in the presence of SB203580, p38 MAP kinase specific inhibitor, a reduced rate of CREB phosphorylation as well as a lower percentage of CD71/Gly+ (Glycophorin A) cells were detectable, demonstrating the p38 MAP kinase dependency of these phenomena. All in all these results document a novel relationship between CREB activation and differentiation-related apoptotic cell death and assign a role to p38 MAP kinase pathway in determining these events in K562 erythroleukemia cells.

VLA-5-mediated Adhesion to Fibronectin Accelerates Hemin-stimulated Erythroid Differentiation of K562 Cells through Induction of VLA-4 Expression

“…Several previous studies demonstrated that activation of p38 and/or JNK but not ERK is required for erythroid differentiation induced by butyrate (30), erythropoietin (32), hydroxyurea (33), or hemin (34). In the present study, siRNA-based downregulation of p38 (Fig.…”

Role of CREB Protein Family Members in Human Haematological Malignancies

“…In another model under investigation in our laboratories and represented by K562 erythroleukaemia cells induced to differentiation [21], the nuclear localization of the active form of CREB was clearly evident after only 1 h treatment with haemin. Interestingly, CREB positive nuclei resembled the features of apoptotic nuclei, suggesting that CREB phosphorylation is possibly required to determine the nuclear structural changes occurring during erythroblast maturation [21,22]. Concerning other family members, it has been recently shown that ATF-2 is a nucleocytoplasmic shuttling protein and that its subcellular localization is regulated by AP-1 dimerization [23].…”

“…Indeed, both under normal or low serum culture conditions an evident nuclear translocation of phospho-CREB was detected after 1 h treatment only with the lower dose of TRAIL (100 ng/mL) and prevented in the presence of PI3K/Akt and p38 mitogen-activated protein kinase (MAPK) specific inhibitors [20]. In another model under investigation in our laboratories and represented by K562 erythroleukaemia cells induced to differentiation [21], the nuclear localization of the active form of CREB was clearly evident after only 1 h treatment with haemin. Interestingly, CREB positive nuclei resembled the features of apoptotic nuclei, suggesting that CREB phosphorylation is possibly required to determine the nuclear structural changes occurring during erythroblast maturation [21,22].…”

“…In our laboratory we have investigated the role of PI3K/Akt pathway and CREB family members in a number of lymphoid and erythroleukaemia cell lines treated with chemical and physical agents inducing cell death by apoptosis or necrosis [20,21,47,[77][78][79][80]. We first detected with Western Blotting a high constitutive level of CREB phosphorylation at Ser133 in Jurkat T cells under normal serum culture conditions [20].…”

α-1,6-Fucosyltransferase (FUT8) Inhibits Hemoglobin Production during Differentiation of Murine and K562 Human Erythroleukemia Cells

“…Sodium butyrate and hemin also induce erythroid differentiation of K562 cells (30 -32). In a phenotypic analysis of K562 cells, the rate of formation of transferrin receptor (CD71)/glycophorin A-positive cells was increased by hemin-mediated induction of differentiation (33). During erythroid differentiation, CD71 is highly expressed in the pre-proerythroblast and the erythroblasts that follow, whereas glycophorin A expression is delayed relative to CD71 and correlates with the transition from the pro-erythroblast to the basophilic normoblast (34).…”