Genetic pathways of replicative senescence and its function in tumorigenesis

描述(申请人提供)：为了维持组织的动态平衡和正常的功能，受损的细胞需要更换或修复。在哺乳动物中，这一过程需要广泛的细胞增殖。这种大规模增殖的结果是突变的积累，其中一些可能针对致癌基因。为了抑制癌前细胞的增殖和存活，有效的肿瘤抑制机制必须是有效的，其中之一就是衰老。衰老限制了细胞的增殖能力，从而阻碍了肿瘤发生所必需的多种突变的积累。此外，异常的致癌激活、DNA损伤或氧化应激也可以激活衰老，提供一种故障保护机制，防止处于肿瘤转化风险的细胞的增殖。克服衰老是癌细胞获得的一种基本特性。尽管衰老的分子调控很重要，但人们对其知之甚少，许多关键的调控因子仍未确定。我们的长期目标是了解衰老的分子调控及其在肿瘤发生中的作用。我们最近发现SMurf2是一种新的衰老调节因子。在人类成纤维细胞中，它的表达随着端粒缩短而上调，这种上调的表达足以诱导衰老。我们的初步研究发现，SMurf2的下调可以延缓人成纤维细胞的衰老，而缺乏SMurf2的小鼠胚胎成纤维细胞在培养中是永生的。我们推测SMurf2通过调节p16和p21衰老途径来调节衰老，因此可能在肿瘤的发生中发挥重要作用。在这个提案中，我们将以三个特定的目标来描述SMurf2在衰老调节和肿瘤发生中的功能。在目标1中，我们将研究SMurf2在调节p16衰老途径中的功能。在目标2中，我们将研究SMurf2调节p21衰老途径的机制。在目标3中，我们将研究SMurf2在肿瘤发生中的功能及其对衰老的调节。这些研究将为SMurf2在肿瘤发生中的作用提供直接证据。此外，这些研究将确定衰老途径中的新遗传成分，并为衰老是如何调节的提供新的见解，这是朝着实现衰老在癌症治疗中的巨大希望迈出的重要一步。公共卫生相关性：拟议的研究将极大地促进我们对衰老的分子调控及其在癌症中的作用的理解。这些认识不仅对开发针对衰老反应的有效治疗方法和利用这种癌症治疗策略提高临床效益具有重要影响，而且还将对理解癌症与衰老的关系，实现预防或改善癌症引起的年龄相关性衰弱具有重要意义。

DESCRIPTION (provided by applicant): To maintain tissue homeostasis and normal functions, damaged cells need to be replaced or repaired. In mammals, such process requires extensive cell proliferation. A consequence of this massive proliferation is the accumulation of mutations, some of which may target cancer causing genes. To constrain the proliferation and survival of precancerous cells, potent tumor suppression mechanisms must be functional, one of which is senescence. Senescence limits proliferative capacity of cells, thus impeding the accumulation of multiple mutations that are necessary for tumorigenesis. Furthermore, aberrant oncogenic activation, DNA damage or oxidative stress can also activate senescence, providing a failsafe mechanism that prevents the proliferation of cells at risk for neoplastic transformation. Overcoming senescence is an essential property acquired by cancer cells. Despite its importance, the molecular regulation of senescence is poorly understood, and many of the critical regulators remain unidentified. Our long-term goal is to understand the molecular regulation of senescence and its function in tumorigenesis. We recently have identified Smurf2 as a novel regulator of senescence. Its expression is up-regulated in response to telomere shortening in human fibroblasts, and such elevated expression is sufficient to induce senescence. Our preliminary studies have found that down-regulation of Smurf2 postpones senescence in human fibroblasts, whereas mouse embryonic fibroblasts deficient in Smurf2 are immortal in culture. We hypothesize that Smurf2 regulates senescence through its ability to modulate the p16 and p21 senescence pathways, and that consequently Smurf2 might play an important role in tumorigenesis. In this proposal, we will characterize the function of Smurf2 in senescence regulation and tumorigenesis with three specific aims. In Aim 1, we will characterize the function of Smurf2 in regulation of the p16 senescence pathway. In Aim 2, we will study the mechanism by which Smurf2 regulates the p21 senescence pathway. In Aim 3, we will investigate the function of Smurf2 and its regulation of senescence in tumorigenesis. These studies will provide direct evidence for a function of Smurf2 in tumorigenesis. Furthermore, these studies will identify new genetic components in the senescence pathways, and provide new insight into how senescence is regulated, an important step towards the fulfillment of the great promise of senescence in cancer treatment. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly advance our understanding of the molecular regulation of senescence and its function in cancer. Such knowledge will have an important impact on not only the development of effective therapies targeting the senescence response and the advancement of clinical benefit utilizing such strategy for cancer treatment, but also the understanding of the relationship between cancer and aging, which is important for achieving prevention or amelioration of age-related debilitation caused by cancer.