ARF AS A THERAPEUTIC AGENT IN ORAL MALIGNANCIES

描述(摘自《调查者摘要》)：口腔鳞状细胞 癌症(SCC)是一种使人虚弱和致命的疾病。尽管取得了进展，但 在传统治疗方法中，口腔癌的发病率仍然令人难以接受， 死亡率。鉴于现有治疗方法的预后较差， 首席调查员的研究将集中在开发更有效的 治疗的前提是逆转细胞的凋亡和增殖缺陷 SCC。INK4a/ARF基因座是第二个最常发生改变的基因 基因在人类癌症中的作用，并在80%的鳞癌中发生改变，这表明它在 这种肿瘤类型的发病机制。利用可选的读框， 哺乳动物的ARF-INF4a基因座编码两种不相关的蛋白质，这两种蛋白质都在 肿瘤抑制。P16INK4a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依赖的激酶活性而处于抑制状态， 而ARF与MDM2结合并阻止MDM2和P53核输出，因此 P53的胞质降解。这些发现表明Ink4a和ARF在 抑制鳞状细胞癌的发展。此前，首席调查员和 他的同事(Zhang等人，1999 a)和其他人(Pmerantz等人，1998)发现 ARF与MDM2癌蛋白结合导致稳定和 P53的转录激活，导致增殖停滞。 最近，首席调查员和同事发现，许多人 人类ARF外显子2癌源性突变破坏其正常核仁 本地化并削弱其阻止MDM2和P53核出口的能力 (Zhang等，1999b)提供了ARF介导的分子机制 P53的稳定和激活与ARF在肿瘤中的作用 压制。这项提案中提出的初步结果确定了两个 ARF未知的功能：ARF引起S期停搏 不依赖于P53，ARF的细胞凋亡反应可以被 功能性视网膜母细胞瘤(RB)蛋白。后来的发现表明 ARF可能选择性地以Rb功能改变的细胞为靶点 凋亡细胞死亡，而正常细胞幸免于难。这项提议的目标是 为了进一步确定ARF诱导的细胞凋亡，ARF的P53独立功能，以及 确定ARF基因治疗口腔鳞癌的可能性 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.