title: Transcriptional mechanism of vascular endothelial growth factor-induced expression of protein kinase CβII in chronic lymphocytic leukaemia cells.
abstract: A key feature of chronic lymphocytic leukaemia (CLL) cells is overexpressed protein kinase CβII (PKCβII), an S/T kinase important in the pathogenesis of this and other B cell malignancies. The mechanisms contributing to enhanced transcription of the gene coding for PKCβII, PRKCB, in CLL cells remain poorly described, but could be important because of potential insight into how the phenotype of these cells is regulated. Here, we show that SP1 is the major driver of PKCβII expression in CLL cells where enhanced association of this transcription factor with the PRKCB promoter is likely because of the presence of histone marks permissive of gene activation. We also show how vascular endothelial growth factor (VEGF) regulates PRKCB promoter function in CLL cells, stimulating PKCβ gene transcription via increased association of SP1 and decreased association of STAT3. Taken together, these results are the first to demonstrate a clear role for SP1 in the up regulation of PKCβII expression in CLL cells, and the first to link SP1 with the pathogenesis of this and potentially other B cell malignancies where PKCβII is overexpressed.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Ola
authors.initials: O
authors.lastname: Al-Sanabra
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Duckworth
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Glenn
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Benjamin R B
authors.initials: BR
authors.lastname: Brown
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Piera
authors.initials: P
authors.lastname: Angelillo
authors.affiliation: Department of Medicine, Roswell Park Cancer Center, Elm and Carlton St, Buffalo, NY, 14263, USA.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Technology Directorate Computational Biology Facility, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7ZB, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Herbert
authors.affiliation: Technology Directorate Computational Biology Facility, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7ZB, United Kingdom.|Department of Functional and Comparative Genomics, University of Liverpool Biosciences, Building, Crown Street, Liverpool, L69 7ZB, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kalakonda
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool. 1st Floor Sherrington Building, Ashton Street, Liverpool, L69 3GE, United Kingdom.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Slupsky
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D064546:Protein Kinase C beta / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C579054:PRKCB protein, human; D064546:Protein Kinase C beta