VRK1 phosphorylates CREB and mediates CCND1 expression.
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.
Kang
Tae-Hong
TH
Department of Life Science, Pohang University of Science and Technology , Pohang 790-784, Republic of Korea.
Park
Do-Young
DY
Kim
Wanil
W
Kim
Kyong-Tai
KT
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
C530104:CCND1 protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human