title: 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.affiliation: Department of Dermatology, Cutaneous Oncology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.forename: Hisato
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Chuan Ping
authors.initials: CP
authors.lastname: Si
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Jin
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jillian
authors.initials: J
authors.lastname: Richmond
authors.forename: Marina
authors.initials: M
authors.lastname: Tuzova
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilson
authors.forename: Beth
authors.initials: B
authors.lastname: Sullivan
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Nataliya
authors.initials: N
authors.lastname: Ryzhenko
authors.forename: Frederick
authors.initials: F
authors.lastname: Little
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: David M
authors.initials: DM
authors.lastname: Center
authors.forename: William W
authors.initials: WW
authors.lastname: Cruikshank
mesh_terms: D021581:Active Transport, Cell Nucleus; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D050883:HSC70 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D019410:Interleukin-16 / Q000235:genetics* / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis / Q000502:physiology; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D012751:Sezary Syndrome / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D019410:Interleukin-16; D009363:Neoplasm Proteins; D011498:Protein Precursors; D044786:S-Phase Kinase-Associated Proteins; C105950:interleukin 16 precursor; D050760:Cyclin-Dependent Kinase Inhibitor p27
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