Mono- or Double-Site Phosphorylation Distinctly Regulates the Proapoptotic Function of Bax

dc.contributor.author

Wang, Qinhong

dc.contributor.author

Sun, Shi-Yong

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Khuri, Fadlo

dc.contributor.author

Curran, Walter J

dc.contributor.author

Deng, Xingming

dc.date.accessioned

2011-06-21T17:32:17Z

dc.date.available

2011-06-21T17:32:17Z

dc.date.issued

2010

dc.description.abstract

Bax is the major multidomain proapoptotic molecule that is required for apoptosis. It has been reported that phosphorylation of Bax at serine(S) 163 or S184 activates or inactivates its proapoptotic function, respectively. To uncover the mechanism(s) by which phosphorylation regulates the proapoptotic function of Bax, a series of serine (S)-> alanine/glutamate (A/E) Bax mutants, including S163A, S184A, S163E, S184E, S163E/S184A (EA), S163A/S184E (AE), S163A/S184A (AA) and S163E/S184E (EE), were created to abrogate or mimic, respectively, either single or double-site phosphorylation. The compound Bax mutants (i.e. EA and AE) can flesh out the functional contribution of individual phosphorylation site(s). WT and each of these Bax mutants were overexpressed in Bax(-/-) MEF or lung cancer H157 cells and the proapoptotic activities were compared. Intriguingly, expression of any of Bax mutants containing the mutation S -> A at S184 (i.e. S184A, EA or AA) represents more potent proapoptotic activity as compared to WT Bax in association with increased 6A7 epitope conformational change, mitochondrial localization/insertion and prolonged half-life. In contrast, all Bax mutants containing the mutation S -> E at S184 (i.e. S184E, AE or EE) have a mobility-shift and fail to insert into mitochondrial membranes with decreased protein stability and less apoptotic activity. Unexpectedly, mutation either S -> A or S -> E at S163 site does not significantly affect the proapoptotic activity of Bax. These findings indicate that S184 but not S163 is the major phosphorylation site for functional regulation of Bax's activity. Therefore, manipulation of the phosphorylation status of Bax at S184 may represent a novel strategy for cancer treatment.

dc.description.version

Version of Record

dc.identifier.citation

Wang,Qinhong;Sun,Shi-Yong;Khuri,Fadlo;Curran,Walter J.;Deng,Xingming. 2010. Mono- or Double-Site Phosphorylation Distinctly Regulates the Proapoptotic Function of Bax. Plos One 5(10): e13393-e13393.

dc.identifier.issn

1932-6203

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https://hdl.handle.net/10161/4578

dc.language.iso

en_US

dc.publisher

Public Library of Science (PLoS)

dc.relation.isversionof

10.1371/journal.pone.0013393

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Plos One

dc.subject

mitochondrial-membrane permeabilization

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cytochrome-c release

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bcl-x-l

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cell-death

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conformational-change

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bh3 domains

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apoptosis

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protein

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activation

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survival

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biology

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multidisciplinary sciences

dc.title

Mono- or Double-Site Phosphorylation Distinctly Regulates the Proapoptotic Function of Bax

dc.title.alternative
dc.type

Other article

duke.date.pubdate

2010-10-14

duke.description.issue

10

duke.description.volume

5

pubs.begin-page

e13393

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