title: Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression.
abstract: VRK2 is a novel Ser-Thr kinase whose VRK2A isoform is located in the endoplasmic reticulum and mitochondrial membranes. We have studied the potential role that VRK2A has in the regulation of mitochondrial-mediated apoptosis. VRK2A can regulate the intrinsic apoptotic pathway in two different ways. The VRK2A protein directly interacts with Bcl-xL, but not with Bcl-2, Bax, Bad, PUMA or Binp-3L. VRK2A does not compete with Bax for interaction with Bcl-xL, and these proteins can form a complex that reduces apoptosis. Thus, high VRK2 levels confer protection against apoptosis. In addition, VRK2 knockdown results in an increased expression of BAX gene expression that is mediated by its proximal promoter, thus VRK2A behaves as a negative regulator of BAX. Low levels of VRK2A causes an increase in mitochondrial Bax protein level, leading to an increase in the release of cytochrome C and caspase activation, detected by PARP processing. VRK2A loss results in an increase in cell death that can be detected by an increase in annexinV+ cells. Low levels of VRK2A increase cell sensitivity to induction of apoptosis by chemotherapeutic drugs like camptothecin or doxorubicin. We conclude that VRK2A protein is a novel modulator of apoptosis.
authors: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
authors: D M
authors: DM
authors: Monsalve
authors: T
authors: T
authors: Merced
authors: I F
authors: IF
authors: Fernández
authors: S
authors: S
authors: Blanco
authors: M
authors: M
authors: Vázquez-Cedeira
authors: P A
authors: PA
authors: Lazo
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004317:Doxorubicin; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C109891:VRK2 protein, human; D020169:Caspases; D002166:Camptothecin