VRK1 phosphorylates CREB and mediates CCND1 expression

Abstract

Vaccinia virus B1 kinase plays a key role in viral DNA replication. The homologous mammalian vaccinia-related kinases (VRKs) are also implicated in the regulation of DNA replication, although direct evidence remains elusive. Here we show that VRK1 regulates cell cycle progression in the DNA replication period by inducing cyclin D1 (CCND1) expression. Furthermore, depletion of VRK1 in human cancer cells reduces the fraction of cells in S phase at a given time. VRK1 specifically enhances activity of the cAMP-response element (CRE) in the CCND1 promoter by facilitating the recruitment of phospho-CREB to this locus. VRK1 phosphorylates CREB at Ser133 in vitro and the expression of a kinase-dead mutant of VRK1 or knockdown of VRK1 using siRNA fails to activate CREB and subsequently activate CRE. Finally, we show that VRK1 is a critical link in the CCND1 gene expression pathway stimulated by Myc overexpression. Our results indicate that VRK1 is a novel regulator of CCND1 expression.

Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

“…Therefore, we determined whether VRK1 knockdown (17,23) would affect focus formation in DDR by detecting the assembly of 53BP1 into IR-induced foci in A549 cells (9). VRK1 knockdown causes entry of the cells in G 0 even in the presence of serum, which cannot revert this cell cycle arrest (23) because VRK1 is required for cyclin D1 gene expression (48). Notably, following irradiation, we observed a decrease in 53BP1 focus formation in siVRK1-02- (Fig.…”

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

“…In addition, mutated p53 can sequester VRK1 from its participation in other transcriptional complexes, such as those between VRK1 and Jun [25], ATF2 [26] or CREB [24] and therefore might affect the expression of genes regulated by these transcription factors.…”

“…VRK1, the most abundant Ser-Thr kinase in nuclei [23], is a nucleosomal/chromatin kinase that can form complexes and phosphorylate several transcription factors [24][25][26], histones [18,[27][28][29] and other chromatin proteins [30,31]. Moreover, VRK1 kinase activity can also be regulated by these proteins interactions, including those with histones [28][29][30].…”

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

“…21 Moreover, loss of VRK1 causes a block in cell cycle progression. 31 The protein is involved in transcriptional activation of cell proliferation genes such as cyclin D1, RB (retinoblastoma), CDK2 (cyclindependent kinase-2), and survivin; 31 VRK1 is also known to phosphorylate CREB (Ser133), 32 BAF (barrier-to-autointegration factor), 33 p53 (Thr18), 34 c-Jun 35 and ATF2 (activating transcription factor 2). 36 Here, we demonstrated that VRK1 from infected cells is much less active in terms of its histone kinase activity than VRK1 immunoprecipitated from untreated cells.…”