Intercellular trafficking of the nuclear oncoprotein DEK

Abstract

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...

The human oncoprotein and chromatin architectural factor DEK counteracts DNA replication stress

“…As we have shown recently that recombinant DEK, added directly to the cell culture medium, passes the cell membrane, enters the nucleus and reengages in its bona fide biological functions, we used this elegant approach for rescue purposes. 11 Indeed, re-added DEK suppressed the formation of 53BP1 nuclear bodies in APH-treated shDEK cells to a level comparable to control cells (Figure 3f). These data evince a role of DEK in safeguarding daughter cells from the consequences of replication-associated DNA damage.…”

“…In cells that have undergone malignant changes that result in accelerated proliferation, such as oncogene activation, the properties of DEK unveiled by our study may favor genomic restabilization and contribute to overcome the DNA damage barrier of oncogenesis (Figure 4f). Furthermore, extracellular DEK-either actively secreted or released by dying cells 11,12,39 -once taken up by neighboring cells may render them more resistant to replication stress-induced DNA damage and less sensitive towards chemotherapeutic agents interfering with DNA replication thereby negatively influencing tumor prognosis.…”

DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML)

“…It has been shown recently by the addition of exogenous recombinant DEK that it can also mediate functions of hematopoietic stem cells (HSC) by suppressing proliferation of hematopoietic progenitor cells (HPC) and enhancing engraftment of long term repopulating cells [17,18]. Interestingly, DEK added to cells is taken up in a bioactive form, moved to the nucleus and re-engages in its bona fide chromatin functions, thus suggesting the existence of a paracrineloop-like mechanism [19]. Furthermore, DEK works in concert with the transcription factor C/EBPα, whose function can be impaired in AML [20].…”

KNIME for reproducible cross-domain analysis of life science data

“…The success of this workflow-based and integrative approach for the field of bioimage analysis has already been proven several times: a diversity of projects are using KNIME Image Processing in multiple application scenarios, ranging from medium to large-scale highthroughput bioimage analysis (Saha et al, 2013;Lodermeyer et al, 2013;Aligeti et al, 2014) to automated microscopy (Gunkel et al, 2014).…”