Tumor suppression by chromatin regulators.

细胞衰老是一种不可逆的细胞生长停滞，阻止受损癌前细胞的增殖。例如，良性的人体痣？或痣-含有受损的癌前色素黑素细胞。痣很少发展成癌症，因为黑素细胞处于生长停滞的衰老状态。染色质是紧密包装在细胞核中的DNA和蛋白质的复杂基质。遗传信息被编码在DNA中。另外的表观遗传信息编码在蛋白质和更高级的折叠模式中，也有助于染色质。遗传和表观遗传信息对于适当的细胞、组织和生物体功能都很重要，并且任何一种的失调都可能导致疾病状态，例如癌症。表观遗传学信息是癌症研究的一个有吸引力的目标，因为表观遗传学改变被认为比遗传学改变更可逆，因此是设计抗癌疗法的理论基础。本申请研究了两种染色质调节复合物（HUCA复合物和Brg 1/Snf 5复合物）的作用，这两种复合物通过其激活细胞衰老的能力而参与癌症的抑制。我们实验室最近的全基因组分析揭示了HUCA和Brg 1/Snf 5复合物之间可能的功能联系。本申请的目的是剖析HUCA和Brg 1/Snf 5合作调节染色质结构并诱导细胞衰老和肿瘤抑制的机制。特别值得注意的是，Snf 5蛋白的失活是儿童恶性横纹肌样瘤的主要原因。这项研究应该加强我们对这种癌症和其他癌症的理解，从而促进改进诊断，预后和治疗策略的发展。

Cell senescence is an irreversible cell growth arrest that stops proliferation of damaged pre-cancerous cells. For example, benign human moles ? or nevi - contain damaged pre-cancerous pigmented melanocytes. Nevi rarely progress to cancer because the melanocytes are held in a growth arrested senescent state. Chromatin is a complex matrix of DNA and proteins packaged tightly into the cell nucleus. Genetic information is encoded within the DNA. Additional epigenetic information is encoded within the proteins and higher order folding patterns that also contribute to chromatin. Both genetic and epigenetic information are important for proper cell, tissue and organismal function, and dysregulation of either can contribute to disease states, such as cancer. Epigenetic information is an attractive target for cancer research, because epigenetic alterations are thought to be more reversible than genetic ones, and so are a rationale basis for design of anti-cancer therapies. This application investigates the role of two chromatin regulatory complexes, the HUCA complex and the Brg1/Snf5 complex, that are implicated in suppression of cancer by virtue of their ability activate cell senescence. Recent whole genome analyses from our lab have uncovered a likely functional link between the HUCA and Brg1/Snf5 complexes. The goal of this application is to dissect the mechanisms by which HUCA and Brg1/Snf5 collaborate to regulate chromatin structure and induce cell senescence and tumor suppression. Of particular note, inactivation of the Snf5 protein is a primary cause of malignant rhabdoid tumors in children. This research should enhance our understanding of this and other cancers, and so promote development of improved diagnostic, prognostic and therapeutic strategies.