title: Functional interplay of SP family members and nuclear factor Y is essential for transcriptional activation of the human Calreticulin gene.
abstract: Calreticulin (CALR) is a highly conserved, multifunctional protein involved in a variety of cellular processes including the maintenance of intracellular calcium homeostasis, proper protein folding, differentiation and immunogenic cell death. More recently, a crucial role for CALR in the pathogenesis of certain hematologic malignancies was discovered: in clinical subgroups of acute myeloid leukemia, CALR overexpression mediates a block in differentiation, while somatic mutations have been found in the majority of patients with myeloproliferative neoplasms with nonmutated Janus kinase 2 gene (JAK2) or thrombopoietin receptor gene (MPL). However, the mechanisms underlying CALR promoter activation have insufficiently been investigated so far. By dissecting the core promoter region, we could identify a functional TATA-box relevant for transcriptional activation. In addition, we characterized two evolutionary highly conserved cis-regulatory modules (CRMs) within the proximal promoter each composed of one binding site for the transcription factors SP1 and SP3 as well as for the nuclear transcription factor Y (NFY) and we verified binding of these factors to their cognate sites in vitro and in vivo.
authors.affiliation: Department of Medical Oncology, University Hospital and University of Bern, 3010 Bern, Switzerland. Electronic address: julian.schardt@insel.ch.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Schardt
authors.affiliation: Department of Medical Oncology, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Medical Oncology, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Seipel
authors.affiliation: Department of Medical Oncology, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
mesh_terms: D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D037282:Calreticulin / Q000235:genetics*; D045744:Cell Line, Tumor; D004247:DNA; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012689:Sequence Homology, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D023081:CCAAT-Binding Factor; D037282:Calreticulin; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D004247:DNA
keywords: Core promoter; NFY; SP1; cis-Regulatory module