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Pro-IL-16 Recruits Histone Deacetylase 3 to the Skp2 Core Promoter through Interaction with Transcription Factor GABP¹

Yujun Zhang^2,*, Marina Tuzova^*, Zhi-Xiong J. Xiao, William W. Cruikshank^* and David M. Center^*

^* Pulmonary Center and Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118

Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished in close correlation to the down-regulation of p27^KIP1 protein. In addition, we showed that pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains elusive. In this study, we identified GA binding protein β1 subunit (GABPβ1) and histone deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPβ1 and HDAC3 have canonical PDZ-binding motifs and specifically bind to the first and second PDZ domain of pro-IL-16, respectively. Heat shock cognate protein 70 (HSC70) also copurified with the GST-PDZ1-containing fragment but lacks a C-terminal PDZ binding motif, suggesting that it binds through a different mechanism. We further showed that pro-IL-16 is located in a GABP transcriptional complex bound to the Skp2 promoter. In addition, we demonstrated that HDAC activity is critical for pro-IL-16-induced cell cycle arrest. Taken altogether, these data suggest that pro-IL-16 forms a complex with GABPβ1 and HDAC3 in suppressing the transcription of Skp2. Thus, this study has revealed a novel mechanism with which pro-IL-16 regulates T cell growth through the Skp2-p27^KIP1 pathway.

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.

¹ This work was supported by National Institutes of Health Grants R01 HL32802 and R01 AI35680 (to D.M.C.), and R01 CA100925 (to Y.Z.).

² Address correspondence and reprint requests to Dr. Yujun Zhang, Pulmonary Center, R-304, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail address: yujunz{at}bu.edu

³ Abbreviations used in this paper: GABP, GA-binding protein; ChIP, chromatin immunoprecipitation; HDAC3, histone deacetylase; HSC70, heat shock cognate protein 70; NLS, nuclear localization signal; PVDF, polyvinylidene difluoride; TSA, trichostatin A.