title: RCAN1 is an important mediator of glucocorticoid-induced apoptosis in human leukemic cells.
abstract: Glucocorticoid (GC) is a major therapeutic agent for the treatment of leukemia because of its ability to induce apoptosis in lymphoid cells. The mechanism causing apoptosis, however, is still controversial. Since the glucocorticoid receptor is a transcription factor, some of its target genes are expected to be implicated in apoptosis. In this study, using a GC-sensitive human pre-B leukemia cell line, Nalm-6, the FK506 binding protein 51 (FKBP5) and regulator of calcineurin 1 (RCAN1) genes were disrupted by homologous recombination, since the expression of both is up-regulated by GC in GC-sensitive but not in GC-resistant leukemic cell lines. While the disruption of FKBP5 had a marginal effect on GC-induced apoptosis, that of RCAN1 resulted in marked resistance to GC. In addition, overexpression of RCAN1 rendered cells more sensitive to DEX. In RCAN1-disrupted cells, levels of some pro-apoptotic and anti-apoptotic Bcl-2 family proteins were decreased and increased, respectively. Finally, phosphorylation of cAMP-response element binding protein (CREB) and up-regulation of CREB target genes by GC were inhibited by RCAN1 disruption, and treatment with a cAMP-inducing agent, forskolin, restored the sensitivity to GC in RCAN1-disrupted Nalm-6 cells. These findings suggest that up-regulation of RCAN1 expression followed by activation of the CREB pathway is required in GC-induced apoptosis.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagao
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Iwai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyashita
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D059765:Homologous Recombination; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C115163:CREB1 protein, human; C108612:RCAN1 protein, human