Chk2 as a target for regulating senescence in skin neoplasia

描述(由申请人提供)： 非黑色素瘤皮肤癌(NMSCs)在人类人群中比任何其他类型的恶性肿瘤更常见。皮肤暴露在紫外线B(UVB)辐射下会引起DNA损伤，其中最显著的是肿瘤抑制基因P53的突变，该基因被认为是NMSCs发育的始动事件。Chk2是一种关键的DNA损伤信号转导通路，已被证明与P53协同工作。Chk2的突变使人类容易患上各种上皮性癌症。同样，在小鼠皮肤中，Chk2缺乏增加了对电离辐射的抵抗力，并导致在化学致癌方案中增加皮肤肿瘤的形成。细胞周期停滞的实现是一个特别重要的事件，它允许细胞在恢复细胞周期进程之前修复受损的DNA。最近发现Chk2与衰老有关，这是一种终末和不可逆转的生长停滞状态。衰老是一种有效的抗癌程序。大多数传统的诱导细胞凋亡的化疗/放射治疗方法通常会诱导癌细胞衰老。然而，肿瘤细胞环境中衰老的机制尚不清楚。识别能够诱导癌细胞衰老的合成和天然化合物，并确定诱导肿瘤细胞衰老的机制，对于拓宽癌症预防和治疗方案的范围将是重要的。我们的初步结果表明，白藜芦醇，一种从葡萄皮中提取的植物防御素，增加了Chk2，随后诱导了衰老。我们还表明，白藜芦醇介导的、不依赖于p53的p21CIP1和p27KIP1的诱导先于衰老的发生。我们将验证这一假设，即白藜芦醇通过调节Chk2&gt；p21CIP1/p27KIP1信号，以非p53方式发挥衰老诱导剂的作用，这一途径在白藜芦醇介导的UVB诱导的皮肤癌的抑制中起重要作用。我们制定了两个特定的目标来验证我们的假设：目标1的研究将定义Chk2在白藜芦醇介导的衰老中的作用，并证明p21/CIP1和p27KIP1的重要性；目标2的研究将定义导致白藜芦醇诱导p53缺失的小鼠皮肤角质形成细胞衰老的分子信号及其在防止UVB诱导的皮肤癌发生中的作用。

DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs) occur more frequently in the human population than any other type of malignancy. The exposure of skin to solar ultraviolet B (UVB) radiation causes DNA damage, most notably mutations in the p53 tumor suppressor gene, which is considered to be the initiating event for the development of NMSCs. The checkpoint kinase, Chk2, is a key DNA damage signal transducer that has been shown to operate in cooperation with p53. The mutations in Chk2 predispose humans to various epithelial cancers. Similarly, in murine skin, Chk2 deficiency augments resistance to ionizing radiation and results in the increased formation of skin tumors in a chemical carcinogenesis protocol. The implementation of cell cycle arrest is a particularly important event that allows the cells to repair damaged DNA before resuming cell cycle progression. Chk2 has recently been shown to be involved in senescence, a state of terminal and irreversible growth arrest. Senescence is a potent anti-carcinogenic program. Most conventional chemo/radiation modalities of cancer treatment that induce cells to undergo apoptosis are often known to induce senescence in cancer cells. However, the mechanisms of the senescence in the tumor cell environment remain to be determined. Identifying both the synthetic and natural compounds that can induce the senescence program in cancer cells, and determining the mechanisms involved in senescent induction in tumor cells, will be important in broadening the range of cancer prevention and treatment options. Our preliminary results show that resveratrol, a phytoalexin derived from the skin of grapes increases Chk2, followed by the induction of senescence. We also show that resveratrol-mediated, p53-independent induction of p21CIP1 and p27KIP1 precedes the occurrence of senescence. We will test the hypothesis that resveratrol acts as a senescence inducer in a p53-independent manner through the modulation of Chk2>p21CIP1/p27KIP1 signaling, and this pathway significantly contributes to the resveratrol-mediated inhibition of UVB-induced skin cancers. We formulated two specific aims to test our hypothesis: the studies in Aim 1 will define the role of Chk2 in resveratrol-mediated senescence and demonstrate the importance of p21/CIP1 and p27KIP1; and the studies in Aim 2 will define the molecular signaling that leads to resveratrol-induced senescence in p53 null murine skin keratinocytes and its contribution to the prevention of UVB-induced skin carcinogenesis.