Loss of nuclear pro-1L-16 facilitates cell cycle progression in human cutaneous T cell lymphoma

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. H...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-12, Vol.121 (12), p.4838
Main 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
Format: Article
Language:English
Subjects:
Care and treatment
Cell cycle
Diagnosis
Genetic aspects
Growth
Interleukins
Lymphomas
Properties
T cells
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Summary: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.
ISSN:0021-9738
DOI:10.1172/JCI41769