TY - JOUR
T1 - Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling
AU - Li, Weimin
AU - Laishram, Rakesh S.
AU - Ji, Zhe
AU - Barlow, Christy A.
AU - Tian, Bin
AU - Anderson, Richard A.
N1 - Funding Information:
The authors thank Shigeki Miyamoto, Randal Tibbetts, and Jay Yang for comments. This study was supported by an NIH grant (GM051968) to R.A.A.; an NIH grant (GM084089) to B.T.; an AHA Postdoctoral Fellowship (0920072G) to R.S.L.; and a Ruth L. Kirschstein National Research Service Award (F32 G082005) to C.A.B.
PY - 2012/1/13
Y1 - 2012/1/13
N2 - 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 BIKmRNA are controlled by the nuclear PI4,5P 2-regulated poly(A) polymerase Star-PAP downstream of DNA damage. Nuclear PKCδ is a key mediator ofapoptosis, 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 BIK3' 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.
AB - 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 BIKmRNA are controlled by the nuclear PI4,5P 2-regulated poly(A) polymerase Star-PAP downstream of DNA damage. Nuclear PKCδ is a key mediator ofapoptosis, 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 BIK3' 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.
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U2 - 10.1016/j.molcel.2011.11.017
DO - 10.1016/j.molcel.2011.11.017
M3 - Article
C2 - 22244330
AN - SCOPUS:84862908573
SN - 1097-2765
VL - 45
SP - 25
EP - 37
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -