title: Glucocorticoid receptor-mediated transcriptional activation of S100P gene coding for cancer-related calcium-binding protein.
abstract: S100P is a member of the S100 family of calcium-binding proteins involved in calcium sensing and signal transduction. Its abnormal expression and biological activities are linked to tumor phenotype, namely to increased survival, proliferation, invasion and metastatic propensity of tumor cells. Association of S100P with outcome of tumor treatment and preliminary data from S100P promoter analysis prompted us to study regulation of S100P expression by glucocorticoids, which are implicated in tumor response to chemotherapy. We showed that dexamethasone (DX), a representative glucocorticoid, was capable to induce activity of S100P promoter by means of increased expression, nuclear translocation, and transactivation properties of the glucocorticoid receptor (GR). Moreover, DX treatment led to decreased phosphorylation of ERK1/2, reduced transcriptional activity of AP1, and modulated activity of some additional transcription factors. We identified a promoter region responsible for DX-mediated transactivation and proved GR binding to S100P promoter. We found that the effect of DX was enhanced by partial but not complete inhibition of the MAPK/ERK pathway, supporting an active crosstalk between GR and MAPK/ERK signal transduction in control of S100P expression. On the other hand, suppression of GR mRNA level by transient siRNA expression resulted in reduced S100P transcription. The role of GR activation in S100P regulation was supported by co-expression of GR with S100P in cells treated with DX. These data suggest that S100P is a direct transcriptional target of glucocorticoid-mediated signaling in tumor cells that is activated through the interplay of GR and MAPK pathways.
authors.affiliation: Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovak Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Tothova
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Juraj
authors.initials: J
authors.lastname: Kopacek
authors.forename: Jaromir
authors.initials: J
authors.lastname: Pastorek
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.forename: Adriana
authors.initials: A
authors.lastname: Gibadulinova
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; D005419:Flavonoids; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011965:Receptors, Glucocorticoid; C103003:S100P protein, human; D003907:Dexamethasone; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one