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...
The human DEK proto-oncogene is a nucleic acid binding protein with suspected roles in human carcinogenesis, autoimmune disease, and viral infection. Intracellular DEK functions, however, are poorly understood. In papillomavirus-positive cervical cancer cells, downregulation of viral E6/E7 oncogene expression results in cellular senescence. We report here the specific repression of DEK message and protein levels in senescing human papillomavirus type 16-(HPV16-) and HPV18-positive cancer cell lines as well as in primary cells undergoing replicative senescence. Cervical cancer cell senescence was partially overcome by DEK overexpression, and DEK overexpression was sufficient for extending the life span of primary keratinocytes, supporting critical roles for this molecule as a senescence regulator. In order to determine whether DEK is a bona fide HPV oncogene target in primary cells, DEK expression was monitored in human keratinocytes transduced with HPV E6 and/or E7. The results identify high-risk HPV E7 as a positive DEK regulator, an activity that is not shared by low-risk HPV E7 protein. Experiments in mouse embryo fibroblasts recapitulated the observed E7-mediated DEK induction and demonstrated that both basal and E7-induced regulation of DEK expression are controlled by the retinoblastoma protein family. Taken together, our results suggest that DEK upregulation may be a common event in human carcinogenesis and may reflect its senescence inhibitory function.Papillomaviruses are a group of small DNA tumor viruses that induce various benign and malignant epithelial lesions in the infected host (24). Classification of the human papillomaviruses (HPVs) into high-risk versus low-risk types is based upon the likelihood that the associated lesions will progress to malignancy or remain benign. High-risk HPV infections are strongly associated with cervical cancer, causing 15% of female cancer mortality worldwide (13). Over 97% of cervical cancers contain high-risk HPV DNA and express the viral oncogenes E6 and E7. A link between HPV infection and carcinogenesis is further supported by the documented in vitro and in vivo immortalizing and transforming activities of the viral oncoproteins (3,21,39,40,56). Many interactions have been reported between high-risk HPV oncoproteins and host cellular factors, including the targeted degradation of p53 and transcriptional upregulation of telomerase by E6 as well as the interaction with and degradation of retinoblastoma family members by E7 (24).HPV DNA is maintained episomally in benign, precancerous lesions but is generally found integrated into the cellular genome in malignant carcinomas and cell lines derived from them (12, 42). Sustained expression of the immortalizing viral oncogenes and oftentimes the loss of the viral E2 open reading frame are important attributes of such cell lines. The papillomavirus E2 protein is a regulatory factor with multiple roles in the transcription and replication of the viral DNA. Loss of E2 protein expression is likely important in the progre...
Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.
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