ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
Identifieur interne : 001437 ( Main/Exploration ); précédent : 001436; suivant : 001438ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia
Auteurs : Luke R. G. Pike [Royaume-Uni] ; Kanchan Phadwal [Royaume-Uni] ; Anna Katharina Simon [Royaume-Uni] ; Adrian L. Harris [Royaume-Uni]Source :
- Molecular Biology Reports [ 0301-4851 ] ; 2012-12-01.
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Abstract
Abstract: Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.
Url:
DOI: 10.1007/s11033-012-1975-3
Affiliations:
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Harris</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, OX3 9DS, Oxford</wicri:regionArea><placeName><settlement type="city">Oxford</settlement><region type="country">Angleterre</region><region type="comté" nuts="2">Oxfordshire</region></placeName><orgName type="university">Université d'Oxford</orgName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Molecular Biology Reports</title><title level="j" type="sub">An International Journal on Molecular and Cellular Biology</title><title level="j" type="abbrev">Mol Biol Rep</title><idno type="ISSN">0301-4851</idno><idno type="eISSN">1573-4978</idno><imprint><publisher>Springer Netherlands</publisher><pubPlace>Dordrecht</pubPlace><date type="published" when="2012-12-01">2012-12-01</date><biblScope unit="volume">39</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="10811">10811</biblScope><biblScope unit="page" to="10822">10822</biblScope></imprint><idno type="ISSN">0301-4851</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0301-4851</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATF4</term><term>BH3-only protein</term><term>HRK</term><term>Harakiri</term><term>Hypoxia</term><term>Integrated stress response</term><term>Unfolded protein response</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Oxfordshire</li></region><settlement><li>Oxford</li></settlement><orgName><li>Université d'Oxford</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Pike, Luke R G" sort="Pike, Luke R G" uniqKey="Pike L" first="Luke R. G." last="Pike">Luke R. G. Pike</name></region><name sortKey="Harris, Adrian L" sort="Harris, Adrian L" uniqKey="Harris A" first="Adrian L." last="Harris">Adrian L. Harris</name><name sortKey="Harris, Adrian L" sort="Harris, Adrian L" uniqKey="Harris A" first="Adrian L." last="Harris">Adrian L. 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