Role and Regulation of the Human DEK Proto-Oncogene

描述(由申请人提供)：感染高危类型的人乳头瘤病毒(HPV)与宫颈癌的发展密切相关。癌症的发生依赖于病毒E6和E7癌基因在患者体内的持续表达。这些癌基因的转录受病毒E2蛋白的负调控，实际上，E2开放阅读框架的中断通常标志着宫颈病变的致癌进展。当重新引入HPV阳性癌细胞时，E2蛋白通过诱导衰老来抑制细胞生长。E2对E6/E7的抑制是这一过程的必要条件和充分条件，这表明重要的衰老介质必须由病毒癌蛋白控制。以前对表达E2的衰老HeLa细胞的转录组的研究表明，人类dek原癌基因一直受到抑制。DEK的表达与人类的癌症发生有关，然而，对细胞内DEK的功能知之甚少，因此其病理生理作用尚不清楚。我们的数据证明了DEK在E2诱导和复制衰老过程中的抑制作用，并发现该分子作为衰老抑制因子的功能。根据潜在的致癌活性，我们确定DEK是高危HPVE7和腺病毒E1a癌基因的上调靶点。RNA干扰研究表明，DEK的表达对于癌细胞的生存是必要的，此外还发现了抗凋亡活性。这项拨款申请旨在研究正常和病毒癌基因诱导DEK表达的分子机制，区分特定的衰老抑制和抗凋亡DEK功能，并阐明控制各自过程的信号通路。为了评估我们的研究结果对癌症诊断和治疗的潜在相关性，我们将检查在HPV阳性肿瘤中DEK表达是否升高。HPV是美国最常见的性传播病原体，也是宫颈癌的原因，宫颈癌是全球第二大最常见的癌症。我们研究了宫颈癌细胞中细胞基因dek的异常上调和活性。我们将确定HPV E7癌蛋白是如何上调dek的，以及它如何有助于刺激宫颈癌的生长，并可能将其用作宫颈癌和其他癌症患者的诊断标志物和药物靶点。

DESCRIPTION (provided by applicant): Infection with the high risk types of human papillomaviruses (HPVs) is strongly linked to the development of cancers of the uterine cervix. Carcinogenesis depends upon the continuous expression of the viral E6 and E7 oncogenes in the affected individual. Transcription of these oncogenes is negatively regulated by the viral E2 protein, and indeed, disruption of the E2 open reading frame usually marks the carcinogenic progression of cervical lesions. When reintroduced into HPV positive cancer cells, E2 proteins suppress cellular growth through senescence induction. E2 repression of E6/E7 is necessary and sufficient for this process, indicating that important senescence mediators must be controlled by the viral oncoproteins. Previous studies of the transcriptome of E2 expressing, senescent HeLa cells revealed consistent repression of the human DEK proto-oncogene. DEK expression has been associated with human carcinogenesis, however, little is known about intracellular DEK functions and its pathophysiological role is thus not known. Our data demonstrate DEK repression during both E2 induced and replicative senescence, and discover functional roles for this molecule as a senescence inhibitor. In agreement with potential pro-carcinogenic activities, we identify DEK as an upregulated target of the high risk HPV E7 as well as the adenovirus E1A oncogene. RNA interference studies reveal that DEK expression is necessary for cancer cell survival and additionally uncover anti-apoptotic activities. This grant application aims to investigate the molecular mechanism by which normal and viral oncogene induced DEK expression is regulated, to distinguish specific senescence inhibitory from anti-apoptotic DEK functions and to shed light on the signaling pathways that govern the respective processes. To assess the potential relevance of our findings for the diagnosis and treatment of cancer, we will examine whether DEK expression is elevated in HPV positive tumors. HPV is the most frequently sexually transmitted pathogen in the U.S. and the cause of cervical cancer, the second most prevalent cancer worldwide. We study the aberrant upregulation and activity of a cellular gene DEK in cervical cancer cells. We will determine how DEK is upregulated by the HPV E7 oncoprotein and how it may help stimulate cervical cancer growth, with potential implications for its use as a diagnostic marker and drug target in cervical and other cancer patients.