Activating p53 for colorectal cancer prevention

项目概要： p53是一种重要的肿瘤抑制因子，在大多数物种中可以阻止肿瘤的发展， 人类癌症中的失活基因虽然约50%的癌症患者携带突变型p53，但许多肿瘤在 肿瘤发展的早期保留野生型p53。癌症前体中野生型p53的存在 通过激活p53抑制肿瘤的化学预防， 进展MDM 2蛋白是p53的关键负调节因子，在拮抗p53中起主要作用 通过直接互动。阻断MDM 2-p53蛋白-蛋白的小分子MDM 2抑制剂 相互作用将从MDM 2中释放p53，从而恢复野生型p53的肿瘤抑制功能。 我们假设通过阻断MDM 2-p53相互作用增强野生型p53的功能， 使用MDM 2抑制剂的前驱病变是预防癌症的有效方法。我们建议 在ApcMin/+小鼠（一种家族性腺瘤性息肉病模型）中检验这一假设。如果成功，我们的研究将为 癌症化学预防的新途径。

PROJECT SUMMARY: p53 is a crucial tumor suppressor that stops tumor development in most species and is the most frequently inactivated gene in human cancers. Although about 50% of cancer patients harbor mutant p53, many tumors at early stages of tumor development retain wild type p53. The presence of wild-type p53 in cancer precursor lesions presents an excellent opportunity for chemoprevention by activating p53 to suppress tumor progression. The MDM2 protein is a key negative regulator of p53 and plays a primary role in antagonizing p53 through direct interaction. Small molecule MDM2 inhibitors that block the MDM2–p53 protein–protein interaction would liberate p53 from MDM2, thereby restoring the tumor suppressor function of wild-type p53. We hypothesize that enhancement of wild-type p53 functions by blocking MDM2-p53 interaction in precursor lesions using MDM2 inhibitor is an effective approach for cancer prevention. We propose to test this hypothesis in ApcMin/+ mice, a model for familial adenomatous polyposis. If succeed, our study will pave a new way for cancer chemoprevention.