GROWTH CONTROL OF NORMAL AND MALIGNANT KERATINOCYTES

在过去的15年里，我的研究计划的主要目标是 为了阐明烟草诱导的 上呼吸消化道鳞状细胞癌 或子宫颈和正常角质形成细胞。自从1989年我们发现 大多数（如果不是所有的话）SCC细胞系对转化是难治的， 生长因子-β（TGF β）介导的细胞周期阻滞，我们重点关注 特别是在阐明这背后的分子机制， 表型我的长期目标是利用这些信息开发新的 预防和治疗ADT癌症的方法， 与30年前的癌症死亡人数一样多。 在过去三年中，我们取得了重大进展。我们是 第一个发现TGF β II型受体中的错义突变 （TbetaR-II）基因在头颈部SCC细胞中几乎完全消除 TbetaR-II激酶活性和信号传导以及一种新型无义突变 编码宫颈癌组织中截短的可溶性TbetaR-II受体的基因 carcinoma.此外，TbetaR-II mRNA表达的缺失解释了 在大约25%的食管癌中存在TGF β抵抗， 在几乎所有的小细胞肺癌（SCLC）细胞系中。在这 在一项研究中，我们已经确定了3个重复GGC的框内缺失 16例中有6例外显子1中的三核苷酸可能影响 受体的处理，并似乎赋予增加的风险， 宫颈癌的早期症状 我们未来五年的具体目标是： 1.开发和完善必要的试剂和测定，以评估 TGF β信号通路的分子和功能状态， 癌组织标本中的一个全面的方式。 2.为了确定在肿瘤发展和进展的哪个阶段， TGF β信号通路变得失活，并且无论TGF β信号通路是否失活， TGF β抗性克隆的出现与一种 肿瘤微环境中的生物活性TGF β。 3.为了确定TGF β受体中的癌症相关突变如何 基因改变受体的生物化学和生物学特性。 4.开发新的治疗策略，旨在激活 功能缺陷型TbetaR下游的TGF β信号通路 受体。

For the past 15 years, the principal goal of my research program has been to elucidate the biological differences between tobacco-induced squamous cell carcinomas (SCC) of the upper aero-digestive tract (ADT) or cervix uteri and normal keratinocytes. Since our discovery in 1989 that most if not all SCC cell lines are refractory to Transforming Growth Factor-beta (TGFbeta)-mediated cell cycle arrest, we have focused specifically on elucidating the molecular mechanism underlying this phenotype. My long term goal is to use this information to develop novel approaches to the prevention and treatment of ADT cancers which still account for as many cancer deaths as 30 years ago. During the past 3 years, we have made significant progress. We were the first to identify missense mutations in the TGFbeta type II receptor (TbetaR-II) gene in head-&-neck SCC cells that nearly complete abrogate TbetaR-II kinase activity and signaling, and a novel nonsense mutation that encodes a truncated soluble TbetaR-II receptor in a cervical carcinoma. In addition, loss of mRNA expression of TbetaR-II accounts for TGFbeta resistance in approximately 25% of esophageal carcinomas and in nearly all small cell lung carcinoma (SCLC) cell lines. In this study, we have identified an in-frame deletion of 3 repeating GGC trinucleotides in exon 1 in 6 of 16 cases that probably affects the receptor processing and appear to confer an increased risk for the development of cervical cancer. Our specific goals for the coming five years are: 1. To develop and refine the reagents and assays necessary to evaluate the molecular and functional status of the TGFbeta signaling pathway in carcinoma tissue specimens in a comprehensive fashion. 2. To determine at which stage of tumor development and progression the TGFbeta signaling pathway becomes inactivated, and whether or not the emergence of TGFbeta-resistant clones is tied to the presence of a biologically active TGFbeta in the tumor microenvironment. 3. To determine how cancer-associated mutations in TGFbeta receptor genes alter the biochemical and biological properties of the receptors. 4. To develop novel therapeutic strategies designed to activate the TGFbeta signaling pathway downstream of functionally deficient TbetaR receptors.