Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma.

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.

• Authors: Clara Curiel-Lewandrowski, Hisato Yamasaki, Chuan Ping Si, Xiaoyi Jin, Yujun Zhang, Jillian Richmond, Marina Tuzova, Kevin Wilson, Beth Sullivan, David Jones, Nataliya Ryzhenko, Frederick Little, Thomas S Kupper, David M Center, William W Cruikshank
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 12 Pg. 4838-49 (Dec 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 22080865 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• CDKN1A protein, human
• CDKN1B protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• DNA, Neoplasm
• HSC70 Heat-Shock Proteins
• HSPA8 protein, human
• Interleukin-16
• Neoplasm Proteins
• Protein Precursors
• S-Phase Kinase-Associated Proteins
• interleukin 16 precursor
• Cyclin-Dependent Kinase Inhibitor p27

Topics

• Active Transport, Cell Nucleus
• Aged
• Aged, 80 and over
• Amino Acid Sequence
• CD4-Positive T-Lymphocytes (metabolism, pathology)
• Cell Cycle (genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics)
• Cyclin-Dependent Kinase Inhibitor p27 (biosynthesis, genetics)
• DNA, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• HSC70 Heat-Shock Proteins (physiology)
• Humans
• Interleukin-16 (genetics, metabolism)
• Lymphoma, T-Cell, Cutaneous (genetics, metabolism, pathology)
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation
• Neoplasm Proteins (genetics, metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology)
• Protein Precursors (genetics, metabolism)
• Protein Structure, Tertiary
• S-Phase Kinase-Associated Proteins (biosynthesis, physiology)
• Sequence Alignment
• Sequence Analysis, DNA
• Sequence Analysis, Protein
• Sequence Homology, Amino Acid
• Sezary Syndrome (genetics, pathology)
• Skin Neoplasms (genetics, metabolism, pathology)