T cell malignancy is a complex process involved in deregulation of cell proliferation and/or apoptosis, including down-regulation of cyclin-dependent kinase inhibitor p27 KIP1. We have identified a T-cell specific protein p80 pro-IL-16, the precursor of Interleukin-16 (IL-16), as a critical negative regulator for p27 KIP1. P80 pro-IL-16 is a nuclear protein highly expressed in resting T cells but rapidly diminished upon T cell activation. The p80 pro-IL-16 gene is located to Ch15q26.3, a site frequently deleted in human T cell malignancies. We have shown that p80 pro-IL-16 is inactivated, either by deletion or mutation in the p80 pro-IL-16 gene, in four T cell malignant cell lines examined and in human primary T cells derived from Sezary syndrome patients. Ectopic expression of p80 pro-IL-16 specifically suppresses Skp2 expression leading to accumulation of p27 KIP1 and Go/G1 cell cycle arrest. P80 pro-IL-16 contains three PDZ domains, which specifically interact the histone deacetylase 3 (HDAC3) and the transcription factor cAMP responsive element binding protein 3 (CREB3). Together, these data strongly suggest that p80 pro-IL-16 play an important role in T cell malignancy. We hypothesize that (1) p80 pro-lL-16 is an adaptor protein that functions to assembly a nuclear protein complex in repressing Skp2 gene transcription in a histone deacetylase-dependent manner and (2) the loss of P80 pro-IL-16 plays an important role in the development of T cell malignancies.
Two specific aims are proposed in this application including (1) to elucidate the mechanism(s) by which p80 pro-lL-16 regulates p27 KIP1 protein expression; and (2) to investigate the role of p80 pro-lL-16 in the development of T cell malignancies. We will focus on the p80 pro-IL-16-mediated suppression of Skp2 gene transcription and the role of HDAC3/CREB3 in this action.. We will investigate whether p80 pro-IL-16-null mice are predisposed to T cell malignancies induced by the chemical carcinogen N-methyl-N-nitrosourea (MNU). This study will lead to a considerable insight of the role of p80 pro-IL-16 in the T cell cycle regulation and T cell malignancy and help to identify diagnostic and/or therapeutical targets for human T cell malignancies.
| Zhang, Yujun; Tuzova, Marina; Xiao, Zhi-Xiong J et al. (2008) Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP. J Immunol 180:402-8 |
