ARF AS A THERAPEUTIC AGENT IN ORAL MALIGNANCIES

描述（改编自研究者摘要）：口腔鳞状细胞 癌（SCC）是一种使人衰弱和致命的疾病。尽管取得了进展， 尽管常规治疗，口腔癌仍然具有不可接受的发病率， mortality.考虑到现有疗法的不良预后， 主要研究者的研究将集中在开发更有效的 在逆转细胞凋亡和增殖缺陷方面， SCC。INK 4a/ARF基因位点代表了第二个最频繁改变的 基因在人类癌症中存在，并且在80%的SCC中改变，这表明它在癌症中的重要性。 这种肿瘤的发病机制。利用替代的阅读帧， 哺乳动物ARF-INF 4a基因座编码两种不相关的蛋白质， 肿瘤抑制p16 INK 4a维持视网膜母细胞瘤蛋白的生长 通过抑制细胞周期蛋白D-依赖性激酶活性， 而ARF与MDM 2结合并阻断MDM 2和p53核输出， p53的细胞质降解。这些发现暗示INK 4A和ARF在 抑制SCC的发展。此前，首席研究员和 他的同事（Zhang等人，1999 a）和其他（Pomerantz等人，（1998）发现 ARF结合MDM 2癌蛋白，导致稳定， p53的转录激活，导致增殖停滞。 最近，首席研究员和同事们发现， 人类ARF外显子2中的癌症衍生突变破坏其正常核仁 定位并削弱其阻断MDM 2和P53核输出的能力 （Zhang等人，1999 b）提供了一种潜在的ARF介导的 p53的稳定和激活以及强调ARF在肿瘤中的作用 镇压本提案中提出的初步结果确定了两个 ARF以前未被认识的功能：ARF诱导S期阻滞 不依赖于p53，对ARF的凋亡反应可以通过 功能性视网膜母细胞瘤（Rb）蛋白。后来的发现表明， ARF可能选择性靶向Rb功能改变的细胞， 凋亡性细胞死亡而不影响正常细胞。本提案的目标是 进一步确定ARF诱导的细胞凋亡，ARF的p53独立功能， 确定ARF基因治疗在口腔癌治疗中的可能效用， SCC。

DESCRIPTION (adapted from the Investigator's abstract): Oral squamous cell carcinoma (SCC) is a debilitating and deadly illness. Despite advances in conventional therapy, oral cancer continues to have unacceptable morbidity and mortality. Given the poor prognosis associated with existing therapies, the Principal Investigator's studies will focus on developing more effective treatments premised on reversing the apoptotic and proliferative defects in SCC. The INK4a/ARF gene locus represents the second most frequently altered gene in human cancer and is altered in 80% of SCC, suggesting its importance in the pathogenesis of this tumor type. Utilizing alternative reading frames, the mammalian ARF-INF4a locus encodes two unrelated proteins that both function in tumor suppression. p16INK4a maintains the retinoblastoma protein in its growth suppressive state through inhibition of cyclin D-dependent kinase activity, while ARF binds with MDM2 and blocks MDM2 and p53 nuclear export, and thus cytoplasmic degradation of p53. These findings implicate both INK4A and ARF in suppressing the development of SCC. Previously, the Principal Investigator and his colleagues (Zhang et al., 1999a) and others (Pomerantz et al., 1998) found that ARF binds the MDM2 oncoprotein leading to stabilization and transcriptional activation of p53 with a resultant proliferative arrest. Recently, the Principal Investigator and coworkers have found that many cancer-derived mutations in human ARF exon 2 disrupt its normal nucleolar localization and impair its ability to block nuclear export of MDM2 and P53 (Zhang et al., 1999b) providing a molecular mechanism underlying ARF-mediated p53 stabilization and activation and underscoring the function of ARF in tumor suppression. The preliminary results presented in this proposal identify two previously unrecognized functions of ARF: that ARF induces an S-phase arrest independent of p53 and that the apoptotic response to ARF can be antagonized by functional retinoblastoma (Rb) protein. The later finding suggests the possibility that ARF may selectively target cells with altered Rb function for apoptotic cell death while sparing normal cells. The goals of this proposal are to further define ARF induced apoptosis, p53 independent functions of ARF, and to determine the possible utility of ARF gene therapy for the treatment of oral SCC.