Apoptosis Inhibition by the Human DEK Oncoprotein Involves Interference with p53 Functions

Abstract

The DEK proto-oncogene has been associated with human carcinogenesis-either as a fusion with the CAN nucleoporin protein or when transcriptionally upregulated. Mechanisms of intracellular DEK functions, however, have remained relatively unexplored. We have recently demonstrated that DEK expression is induced by the high-risk human papillomavirus (HPV) E7 protein in a manner which is dependent upon retinoblastoma protein function and have implicated DEK in the inhibition of cellular senescence. Additionally, overexpression of DEK resulted in significant life span extension of primary human keratinocytes. In order to determine whether DEK expression is required for cellular proliferation and/or survival, we monitored cellular responses to the knockdown of DEK in cancer and primary cells. The results indicate that DEK expression protects both HPV-positive cancer and primary human cells from apoptotic cell death. Cell death in response to DEK depletion was accompanied by increased protein stability and transcriptional activity of the p53 tumor suppressor and consequent upregulation of known p53 target genes such as p21 CIP and Bax. Consistent with a possible role for p53 in DEK-mediated cell death inhibition, the p53-negative human osteosarcoma cell line SAOS-2 was resistant to the knockdown of DEK. Finally, expression of a dominant negative p53 miniprotein inhibited DEK RNA interference-induced p53 transcriptional induction, as well as cell death, thus directly implicating p53 activation in the observed apoptotic phenotype. These findings suggest a novel role for DEK in cellular survival, involving the destabilization of p53 in a manner which is likely to contribute to human carcinogenesis.The human DEK proto-oncogene was originally identified as a fusion with the CAN nucleoporin protein in a subset of acute myeloid leukemia patients carrying the t(6;9) translocation (50). Since its discovery, DEK has also been found to be transcriptionally upregulated in a number of aggressive human tumors such as bladder carcinoma, hepatocellular carcinoma, glioblastoma, melanoma, and acute myeloid leukemia types that do not exhibit the above translocation (21,29,31,32,44). DEK is a potential target of chromosome 6p22 gains in retinoblastoma, as well as in bladder cancer, suggesting that DEK gain of function may provide a selective advantage for tumor development (15,20,41). Consistent with potential oncogenic DEK properties is the developmental regulation of DEK mRNA with high expression in immature retinal mouse cells and with induced levels of DEK expression in simian virus 40 (SV40) large T antigen-induced retinoblastomas (41). The latter finding may further support our previous results obtained with primary human keratinocytes, where upregulated expression of DEK in response to the SV40 T antigen-related high-risk human papillomavirus (HPV) E7 protein was dependent upon retinoblastoma protein function (59). Furthermore, our data indicated that both the replicative senescence of primary human foreskin keratinocytes (HFKs) and...

DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung

“…Delayed and moderate decrease of cell proliferation and marked reduction of in vitro colony formation activity were observed when DEK was silenced in SCLC cell lines. However, no significant increase of apoptosis or senescence was detected in contrast to previous reports of other cell types, whereas p53 expression was induced in SBC3 cells (Supplementary Figure 4, Wise-Draper et al, 2006, 2009aKhodadoust et al, 2009). This might be because both the RB and p53 pathways are frequently inactivated and could partly complement DEK-mediated anti-apoptotic and anti-senescence function in SCLC cell lines.…”

“…DEK expression is regulated by E2F and overexpression of DEK protein has been reported in several types of solid tumor (Carro et al, 2006). Moreover, DEK inhibits apoptosis by modulating p53 activity and is implicated in cellular senescence/ immortalization (Wise-Draper et al, 2006;Scoumanne and Chen, 2007). It has been reported that DEK has transforming activity in human keratinocytes when working in association with HPV E6/E7 viral oncoproteins or p16 silencing (Wise-Draper et al, 2005, 2009a.…”

The DEK oncoprotein is upregulated by multiple leukemia-associated fusion genes

“…DEK also protects against cell death. Knockdown of DEK increases both p53-dependent andindependent apoptosis as well as the sensitivity to apoptotic agents such as etoposide [4,5].…”

Overexpression of DEK is an indicator of poor prognosis in patients with gastric adenocarcinoma

“…The DEK proto-oncogene (DEK) protein was identified in a subset of patients with acute myeloid leukemia as a fusion gene with nucleoporin 214 (3,4). In the majority of aggressive human tumors, including neuroblastoma, malignant glioma, melanoma, acute adult leukemia, and bladder and cervical cancer, the DEK gene frequently exhibits an increased expression level (5)(6)(7)(8)(9).…”

“…In addition, autoantibodies to DEK have been identified in juvenile rheumatoid arthritis, systemic lupus erythematosus and sarcoidosis. Previous studies have suggested that the DEK protein is closely associated with the apoptosis of cells, since it inhibits p53-mediated apoptosis, it works in combination with the viral oncogenes, E6 and E7, to overcome senescence in cells, and it also promotes Harvey Rat Sarcoma Viral Oncogene Homolog-driven keratinocyte transformation (4,(10)(11)(12). A study by Han et al (13) demonstrated that the DEK protein was closely associated with the proliferation of serous ovarian tumor cells, and that the overexpression of DEK was significantly associated with the increased proliferating index of Ki-67.…”