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- Title
Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma.
- Authors
Curiel-Lewandrowski, Clara; Yamasaki, Hisato; Si, Chuan Ping; Jin, Xiaoyi; Zhang, Yujun; Richmond, Jillian; Tuzova, Marina; Wilson, Kevin; Sullivan, Beth; Jones, David; Ryzhenko, Nataliya; Little, Frederick; Kupper, Thomas S; Center, David M; Cruikshank, William W
- Abstract
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro-IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent-kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro-IL-16. T cells isolated from 11 patients with advanced CTCL, but not those from healthy controls or patients with T cell acute lymphocytic leukemia (T-ALL), demonstrated reduction in nuclear pro-IL-16 levels. Sequence analysis identified the presence of mutations in the 5' end of the PDZ1 region of pro-IL-16, a domain required for association of pro-IL-16 with the nuclear chaperone HSC70 (also known as HSPA8). HSC70 knockdown led to loss of nuclear translocation by pro-IL-16 and subsequent increases in Skp2 levels and decreases in p27Kip1 levels, which ultimately enhanced T cell proliferation. Thus, our data indicate that advanced CTCL cell growth is facilitated, at least in part, by mutations in the scaffold protein pro-IL-16, which directly regulates Skp2 synthesis.
- Publication
The Journal of clinical investigation, 2011, Vol 121, Issue 12, p4838
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI41769