DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2
Identifieur interne : 000678 ( Pmc/Curation ); précédent : 000677; suivant : 000679DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2
Auteurs : Casey M. Clements [États-Unis] ; Richard S. Mcnally [États-Unis] ; Brian J. Conti [États-Unis] ; Tak W. Mak [Canada] ; Jenny P.-Y. Ting [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2006.
Abstract
DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
Url:
DOI: 10.1073/pnas.0607260103
PubMed: 17015834
PubMed Central: 1586179
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<front><div type="abstract" xml:lang="en"><p>DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
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<article-id pub-id-type="doi">10.1073/pnas.0607260103</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
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<title-group><article-title>DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Clements</surname>
<given-names>Casey M.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>McNally</surname>
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<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Conti</surname>
<given-names>Brian J.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Mak</surname>
<given-names>Tak W.</given-names>
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<xref ref-type="aff" rid="aff2"><sup>†</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>‡</sup>
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<contrib contrib-type="author"><name><surname>Ting</surname>
<given-names>Jenny P.-Y.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="corresp" rid="cor1"><sup>‡</sup>
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<aff id="aff1">*Department of Microbiology–Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295; and</aff>
<aff id="aff2"><sup>†</sup>
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1</aff>
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<author-notes><corresp id="cor1"><sup>‡</sup>
To whom correspondence may be addressed. E-mail:
<email>tmak@uhnresearch.ca</email>
or <email>jenny_ting@med.unc.edu</email>
</corresp>
<fn fn-type="con"><p>Contributed by Tak W. Mak, August 22, 2006</p>
</fn>
<fn fn-type="con"><p>Author contributions: C.M.C., T.W.M., and J.P.-Y.T. designed research; C.M.C., R.S.M., and B.J.C. performed research; T.W.M. contributed new reagents/analytic tools; C.M.C., R.S.M., and B.J.C. analyzed data; and C.M.C. and J.P.-Y.T. wrote the paper.</p>
</fn>
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<pub-date pub-type="ppub"><day>10</day>
<month>10</month>
<year>2006</year>
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<pub-date pub-type="epub"><day>2</day>
<month>10</month>
<year>2006</year>
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<volume>103</volume>
<issue>41</issue>
<fpage>15091</fpage>
<lpage>15096</lpage>
<copyright-statement>© 2006 by The National Academy of Sciences of the USA</copyright-statement>
<copyright-year>2006</copyright-year>
<license license-type="open-access"><p>Freely available online through the PNAS open access option.</p>
</license>
<self-uri xlink:title="pdf" xlink:href="zpq04106015091.pdf"></self-uri>
<abstract><p>DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.</p>
</abstract>
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