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（NMSC）在人群中比任何其他类型的恶性肿瘤更常见。皮肤暴露于太阳紫外线B（UVB）辐射会导致DNA损伤，最显著的是p53肿瘤抑制基因的突变，这被认为是NMSC发育的起始事件。检查点激酶Chk 2是一种关键的DNA损伤信号转导子，已被证明与p53协同作用。Chk 2的突变使人类易患各种上皮癌。类似地，在小鼠皮肤中，Chk 2缺乏增强了对电离辐射的抵抗力，并导致在化学致癌方案中皮肤肿瘤的形成增加。细胞周期阻滞的实施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。Chk 2最近被证明与衰老有关，衰老是一种终末和不可逆的生长停滞状态。衰老是一个有效的抗癌计划。通常已知诱导细胞经历凋亡的癌症治疗的大多数常规化疗/放射方式诱导癌细胞的衰老。然而，肿瘤细胞环境中的衰老机制仍有待确定。鉴定可以诱导癌细胞衰老程序的合成和天然化合物，并确定肿瘤细胞衰老诱导的机制，对于扩大癌症预防和治疗选择的范围将是重要的。我们的初步研究结果表明，白藜芦醇，一种来自葡萄皮的植物抗毒素增加Chk 2，随后诱导衰老。我们还表明，白藜芦醇介导的，p53独立的诱导p21 CIP 1和p27 KIP 1之前发生衰老。我们将检验白藜芦醇通过调节Chk 2> p21 CIP 1/p27 KIP 1信号以p53非依赖性方式作为衰老诱导剂的假设，并且该途径显著有助于白藜芦醇介导的UVB诱导的皮肤癌的抑制。我们制定了两个具体的目标来验证我们的假设：目标1中的研究将定义Chk 2在白藜芦醇介导的衰老中的作用，并证明p21/CIP 1和p27 KIP 1的重要性;目标2中的研究将定义导致p53缺失小鼠皮肤角质形成细胞中白藜芦醇诱导衰老的分子信号传导及其对预防UVB诱导的皮肤癌发生的贡献。

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.