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J. Biol. Chem., Vol. 281, Issue 21, 14893-14906, May 26, 2006

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p204 Protein Overcomes the Inhibition of the Differentiation of P19 Murine Embryonal Carcinoma Cells to Beating Cardiac Myocytes by Id Proteins^*

Bo Ding, Chuan-ju Liu, Yan Huang^¶, Jin Yu, Weihua Kong, and Peter Lengyel¹

From the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8024, the Department of Orthopedic Surgery and Cell Biology, New York University School of Medicine, New York, New York 10003, and the ^¶Department of Internal Medicine, Cardiology, Yale University School of Medicine, New Haven, Connecticut 06520-8024

We reported in the accompanying article (Ding, B., Liu, C., Huang, Y., Hickey, R. P., Yu, J., Kong, W., and Lengyel, P. (2006) J. Biol. Chem. 281, 14882-14892) that (i) the p204 protein is required for the differentiation of murine P19 embryonal carcinoma stem cells to beating cardiac myocytes, and (ii) the expression of p204 in the differentiating P19 cells is synergistically transactivated by the cardiac transcription factors Gata4, Nkx2.5, and Tbx5. Here we report that endogenous or ectopic inhibitor of differentiation (Id) proteins inhibited the differentiation of P19 cells to myocytes. This was in consequence of the binding of Id1, Id2, or Id3 protein to the Gata4 and Nkx2.5 proteins and the resulting inhibitions (i) of the binding of these transcription factors to each other and to DNA and (ii) of their synergistic transactivation of the expression of various genes, including atrial natriuretic factor and Ifi204 (encoding p204). p204 overcame this inhibition by Id proteins in consequence of (i) binding and sequestering Id proteins, (ii) accelerating their ubiquitination and degradation by proteasomes, and (iii) decreasing the level of Id proteins in the nucleus by increasing their translocation from the nucleus to the cytoplasm. Points (ii) and (iii) depended on the presence of the nuclear export signal in p204. In the course of the differentiation, Gata4, Nkx2.5, and p204 were components of a positive feedback loop. This loop arose in consequence of it that p204 overcame the inhibition of the synergistic activity of Gata4 and Nkx2.5 by the Id proteins.

Received for publication, October 31, 2005 , and in revised form, February 15, 2006.

^* This work was supported by NIAID Research Grant AI-12320 from the National Institutes of Health. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S.

¹ To whom correspondence should be addressed: Dept. of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar St., New Haven, CT 06520-8024. Tel.: 203-737-2061; Fax: 203-785-7979; E-mail: peter.lengyel{at}yale.edu.

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