DEK is a biochemically distinct, conserved nonhistone protein that is vital to global heterochromatin integrity. In addition, DEK can be secreted and function as a chemotactic, proinflammatory factor. Here we show that exogenous DEK can penetrate cells, translocate to the nucleus, and there carry out its endogenous nuclear functions. Strikingly, adjacent cells can take up DEK secreted from synovial macrophages. DEK internalization is a heparan sulfate-dependent process, and cellular uptake of DEK into DEK knockdown cells corrects global heterochromatin depletion and DNA repair deficits, the phenotypic aberrations characteristic of these cells. These findings thus unify the extracellular and intracellular activities of DEK, and suggest that this paracrine loop involving DEK plays a role in chromatin biology. cellular biology | cancer | autoimmunity | juvenile arthritis S ince its initial cloning as part of the t(6;9) translocation in a subset of patients with acute myelogenous leukemia (1, 2), DEK has been shown to affect global heterochromatin integrity (3), mRNA splicing (4, 5), transcriptional control (both negative and positive) (6-8), DNA damage repair and susceptibility (9, 10), DNA replication (11), cellular differentiation (12, 13), cell viability (8), apoptosis (14), and senescence (15). DEK also plays a key role in the biology of hematopoietic and muscle stem cells (12,16).DEK overexpression occurs in various prevalent and difficult-totreat neoplasms, including hepatocellular carcinoma (17), glioblastoma (18), melanoma (8,19), bladder cancer (20), retinoblastoma (21, 22), breast cancer (23), and T-cell large granular lymphocytic leukemia (24). DEK is degraded by the F-box/tryptophan-aspartic acid (WD) repeat-containing protein 7 (Fbxw7) tumor suppressor, which affects cell division and splicing of messenger RNA (25). Elevated levels of DEK can interfere with cellular differentiation, apoptosis, senescence, and the response to chemotherapy, justifying the classification of DEK as a bona fide oncogene that plays a role in central pathways promoting tumor growth and survival (8,19,23).In addition to its roles in tumor biology, which appear to be related mainly to its intracellular functions, DEK also has been implicated in the pathogenesis of autoimmune disorders, functions more attributable to its extracellular activities (discussed below). In fact, circulating autoantibodies to DEK have been identified in the serum of patients with various autoimmune diseases, including juvenile idiopathic arthritis (JIA), sarcoidosis, and systemic lupus erythematosus (SLE) (26). Furthermore, autoantibodies to DEK, as well as DEK protein itself, have been detected in synovial fluids of children with JIA (27). The presence of DEK protein and DEK autoantibodies in the extracellular space suggests a proinflammatory role for DEK. In fact, on activation, macrophages secrete DEK, which in turn can act as a chemotactic factor for neutrophils, natural killer cells, and cytotoxic T lymphocytes in the extracellular milieu (28). Th...
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