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Increased Expression of Ifi202, an IFN-Activatable Gene, in B6.Nba2 Lupus Susceptible Mice Inhibits p53-Mediated Apoptosis¹

Hong Xin^*, Sanjay D’Souza^2,*, Trine N. Jørgensen, Andrew T. Vaughan^3,*, Peter Lengyel, Brian L. Kotzin^4, and Divaker Choubey^5,*

^* Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153; Division of Clinical Immunology, University of Colorado Health Sciences Center, Denver, CO 80262; and Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520

Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44–83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.

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				R. Panchanathan, H. Xin, and D. Choubey Disruption of Mutually Negative Regulatory Feedback Loop between Interferon-Inducible p202 Protein and the E2F Family of Transcription Factors in Lupus-Prone Mice J. Immunol., May 1, 2008; 180(9): 5927 - 5934. [Abstract] [Full Text] [PDF]

				M. R. Gubbels Bupp, M. Li, A. Pashine, D. Aud, and S. L. Peng The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function Rheumatology, January 1, 2008; 47(1): 103 - 104. [Full Text] [PDF]

				M. Yamauchi, M. Hashimoto, K. Ichiyama, R. Yoshida, T. Hanada, T. Muta, S. Komune, T. Kobayashi, and A. Yoshimura Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/W F1 mice, is a positive regulator for NF-{kappa}B activation in dendritic cells Int. Immunol., August 16, 2007; (2007) dxm054v1. [Abstract] [Full Text] [PDF]