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J. Biol. Chem., Vol. 278, Issue 25, 23008-23019, June 20, 2003

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The Interferon-inducible p202a Protein Modulates NF-B Activity by Inhibiting the Binding to DNA of p50/p65 Heterodimers and p65 Homodimers While Enhancing the Binding of p50 Homodimers^*

Xian-Yong Ma  , Hong Wang  ¶, Bo Ding , Haihong Zhong || **, Sankar Ghosh || and Peter Lengyel  

From the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520 and the ^||Immunobiology Section and Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06520

p202a is a member of the interferon-inducible murine p200 family of proteins. These proteins share 1 or 2 partially conserved 200 amino acid segments of the a or the b type. The known biological activities of p202a include among others the regulation of muscle differentiation, cell proliferation, and apoptosis. These biological activities of p202a can be correlated with the inhibition of the activity of several transcription factors. Thus, the binding of p202a results in the inhibition of the sequence-specific binding to DNA of the c-Fos, c-Jun, E2F1, E2F4, MyoD, myogenin, and c-Myc transcription factors. This study concerns the mechanisms by which p202a inhibits the activity of NF-B, a transcription factor involved among others in host defense, inflammation, immunity, and the apoptotic response. NF-B consists of p50 and p65 subunits. We demonstrate that p202a can inhibit in vitro and in vivo the binding to DNA of p65 homodimers and p50/65 heterodimers, whereas it increases the binding of p50 homodimers. Thus p202a can impair NF-B activity both by inhibiting the binding to DNA of the transcriptionally active p65 homodimers and p50/p65 heterodimers and by boosting the binding of the repressive p50 homodimers. p202a can bind p50 and p65 in vitro and in vivo, and p202a can be part of the p50 homodimer complex bound to DNA. p50 binds in p202a to the a type segment, whereas p65 binds to the b type segment. Transfected ectopic p202a increases the apoptotic effect of tumor necrosis factor (at least in part) by inhibiting NF-B and its antiapoptotic activity.

Received for publication, February 27, 2003

^* This work was supported by postdoctoral fellowships from the Cancer Research Institute (to H. W.) and the Leukemia Society of America (to H. Z.). Support was also obtained from the Howard Hughes Medical Institute (to S. G.) and research grants from the National Institutes of Health (to S. G. and P. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Laboratory Medicine, Yale University, New Haven, CT 06520.

^¶ Present address: Dept. of Surgery, Northshore University Hospital, Northshore LIJ Research Institute, Manhasset, NY 11030.

^** Present address: Curagen Corp., Branford, CT 06405.

To whom correspondence should be addressed: Dept. of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar St., New Haven, CT 06520. Tel.: 203-737-2061; Fax: 203-785-7979; E-mail: peter.lengyel{at}yale.edu.

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