title: Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling.
abstract: BIK protein is an initiator of mitochondrial apoptosis, and BIK expression is induced by proapoptotic signals, including DNA damage. Here, we demonstrate that 3' end processing and expression of BIK mRNA are controlled by the nuclear PI4,5P(2)-regulated poly(A) polymerase Star-PAP downstream of DNA damage. Nuclear PKCδ is a key mediator of apoptosis, and DNA damage stimulates PKCδ association with the Star-PAP complex where PKCδ is required for Star-PAP-dependent BIK expression. PKCδ binds the PI4,5P(2)-generating enzyme PIPKIα, which is essential for PKCδ interaction with the Star-PAP complex, and PKCδ activity is directly stimulated by PI4,5P(2). Features in the BIK 3' UTR uniquely define Star-PAP specificity and may block canonical PAP activity toward BIK mRNA. This reveals a nuclear phosphoinositide signaling nexus where PIPKIα, PI4,5P(2), and PKCδ regulate Star-PAP control of BIK expression and induction of apoptosis. This pathway is distinct from the Star-PAP-mediated oxidative stress pathway indicating signal-specific regulation of mRNA 3' end processing.
authors.affiliation: Department of Pharmacology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Rakesh S
authors.initials: RS
authors.lastname: Laishram
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ji
authors.forename: Christy A
authors.initials: CA
authors.lastname: Barlow
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D004249:DNA Damage; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011062:Polynucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D051745:Protein Kinase C-delta; D009713:Nucleotidyltransferases; C586325:TUT1 protein, human; D011062:Polynucleotide Adenylyltransferase