Burkitt’s淋巴瘤（BL）是一种具高度侵袭力的B细胞性恶性疾病。超保守RNA（UCR）是一类大于200核苷酸，其序列在人、大鼠和小鼠中完全保守的长链非编码RNA。uc.102-106是五个位于同一编码基因ola1中的UCR。我们利用自己建立的p53可控表达的BL动物模型发现，p53激活15分钟后uc.106表达急增数千倍，且uc.106具极强的抑制体内淋巴瘤生长的作用，而uc.102-105四个UCR在p53激活后增高只有几倍。由此我们推测，p53可以通过直接调控特定UCR的转录发挥其抑制肿瘤生长的作用。为此本课题计划研究uc.102-106 1）如何受p53调控；2）在肿瘤中的表达谱；3）在淋巴瘤中作用；4）是否作为反义RNA控制淋巴瘤生长。本项目不仅让我们更深入了解p53新的生物学行为，而且将为受p53调控的UCRs作为新的肿瘤诊断标记，尤其是治疗靶点提供理论依据。

Burkitt’s lymphoma is a highly invasive B-cell malignancy. Ultraconserved RNA is a class of specific long non-coding RNAs whose sequences are completely conserved among human, rat and mouse. uc.102-106 are five UCRs all located in different introns of the same coding gene ola1 (Obg-like ATPase 1). To investigate the molecular mechanism of lymphomagenesis we established a non-transgenic murine system based on the molecular hallmarks of human Burkitt’s lymphoma: over-expression of c-myc oncogene and inactivation of p53 tumor suppressor. To address whether and how p53 regulates its downstream non-coding RNAs, we generated murine lymphomas engineered with P53-estrogen receptor fusion protein (P53ER). In these lymphomas P53 function can be rapidly toggled between "off" and "on" with 4OH-Tamoxifen. Using this system we have found that the expression level of uc.106 located in the fourth intron of ola1 is increased over three thousand times 15 min after p53 activation. Ｗe have also found that uc.106 strongly inhibits the growth of lymphoma cells both in vitro and in vivo, while other UCRs (uc-102, uc-103, uc-104 and uc.105) and the mRNA from their host gene ola1 are increased only slightly after p53 activation. We thus hypothesize that p53 inhibits lymphomagenesis，at least partially through direct transcriptional regulation of UCRs. In this proposal, we plan to examine 1) how p53 regulates the expression of uc.102-106; 2) the expression profile of uc.102-106 in lymphomas and other tumors; 3) the role of uc.102-106 in lymphomagenesis; and 4) whether uc.102-106 act as anti-sense RNA to control the tumorigenesis. This study will not only shed light on the new biology of tumor suppressor p53, but also provide the potential novel diagnostic biomarkers and therapeutic targets for Burkitt’s lymphomas and other related tumors.