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J. Biol. Chem., Vol. 276, Issue 17, 14407-14413, April 27, 2001
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From the Manganese superoxide dismutase
(Mn-SOD) is a primary antioxidant enzyme whose expression is
essential for life in oxygen. Mn-SOD has tumor suppressor activity in a
wide variety of tumors and transformed cell systems. Our initial
observations revealed that Mn-SOD expression was inversely correlated
with expression of AP-2 transcription factors in normal human
fibroblasts and their SV-40 transformed counterparts. Thus we
hypothesized that AP-2 may down-regulate Mn-SOD expression. To examine
the functional role of AP-2 on Mn-SOD promoter transactivation we
cotransfected AP-2-deficient HepG2 cells with a human Mn-SOD
promoter-reporter construct and expression vectors encoding each of the
three known AP-2 family members. Our results indicated that AP-2 could
significantly repress Mn-SOD promoter activity, and that this
repression was both Mn-SOD promoter and AP-2-specific. The three AP-2
proteins appeared to play distinct roles in Mn-SOD gene regulation.
Moreover, although all three AP-2 proteins could repress the Mn-SOD
promoter, AP-2
A Family of AP-2 Proteins Down-regulate Manganese Superoxide
Dismutase Expression*
,§,¶, and¶
Free Radical & Radiation Biology Program,
Department of Radiology, and ¶ Holden Comprehensive Cancer Center,
University of Iowa, Iowa City, Iowa 52242
and AP-2
were more active in this regard than
AP-2
. Transcriptional repression by AP-2 was not a general effect in
this system, because another AP-2-responsive gene, c-erbB-3, was
transactivated by AP-2. Repression of Mn-SOD by AP-2 was dependent on
DNA binding, and expression of AP-2B, a dominant negative incapable of
DNA binding, relieved the repression on Mn-SOD promoter and reactivated Mn-SOD expression in the AP-2 abundant SV40-transformed fibroblast cell
line MRC-5VA. These results indicate that AP-2-mediated
transcriptional repression contributes to the constitutively low
expression of Mn-SOD in SV40-transfromed fibroblasts and suggest a
mechanism for Mn-SOD down-regulation in cancer.
*
This work was supported by United States Public Health
Services Grants CA-73612 (to F. E. D.) and P01 CA-66081 (to
L. W. O.) from the NCI.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Free Radical & Radiation Biology Program, B180 Medical Laboratories, The University of
Iowa, Iowa City, IA 52242. Tel.: 319-335-8018; Fax: 319-335-8039; E-mail: frederick-domann@uiowa.edu.
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