Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling

Weimin Li; Rakesh S. Laishram; Zhe Ji; Christy A. Barlow; Bin Tian; Richard A. Anderson

doi:10.1016/j.molcel.2011.11.017

Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling

Weimin Li, Rakesh S. Laishram, Zhe Ji, Christy A. Barlow, Bin Tian, Richard A. Anderson^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	25-37
Number of pages	13
Journal	Molecular cell
Volume	45
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2011.11.017
State	Published - Jan 13 2012

Funding

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.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2011.11.017

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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 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.",

author = "Weimin Li and Laishram, {Rakesh S.} and Zhe Ji and Barlow, {Christy A.} and Bin Tian and Anderson, {Richard A.}",

note = "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. ",

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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.

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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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Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIα and PKCδ signaling

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