核糖体对于细胞的正常生长至关重要，核糖体生物合成一旦受到抑制会诱导核糖体应激，即核糖体相关蛋白获得新的功能，导致细胞生长、增殖和分化异常。鸟苷酸交换因子SBDS参与rRNA合成和核糖体装配，但在肿瘤中的功能及分子机制尚不清楚。我们通过生物信息学和临床标本分析发现SBDS可能与肿瘤发生和发展相关。在本项目中，一方面我们将探索敲降SBDS能否引发核糖体应激反应，从而激活p53并抑制肿瘤细胞生长。另一方面，探索核糖体应激药物能否诱导SBDS与MDM2蛋白互作并削弱MDM2对p53降解，进而抑制肿瘤细胞生长。还将通过免疫缺陷小鼠荷瘤模型，研究上述两个信号通路对体内成瘤的影响。最后，研究大量临床样本，明确SBDS在结、直肠癌中高表达的临床意义。本项目首次阐明SBDS活化p53的分子机制及其在肿瘤发生和发展中的功能，对结、直肠癌等恶性肿瘤临床治疗具有指导意义。

As the ribosome is crucial to cell growth, perturbation of ribosome biogenesis induces gain-of-functions of ribosome-associated proteins leading to aberrant cell growth, proliferation and differentiation. This process is called ribosomal stress. The ribosome assembly guanine nucleotide exchange factor SBDS is required for rRNA synthesis and ribosome production, whereas, it remains unclear if SBDS is involved in tumorigenesis. Through bioinformatics and tumor sample analyses, we believe that SBDS is associated with cancer development. In this study, we will explore if knockdown of SBDS can trigger ribosomal stress, as thus leading to p53 activation and cell growth arrest. Additionally, we will determine whether ribosomal stress-inducing agents can promote the interaction of SBDS and MDM2, consequently leading to p53 stabilization and cell growth arrest. Furthermore, xenograft experiment will be performed using SCID mice to testify the two pathways in vivo. Lastly, a large number of colorectal cancer samples will be analyzed to unveil the clinical significance of hyperexpression of SBDS in cancer. In sum, this study will demonstrate the molecular basis of SBDS-mediated p53 activation in tumorigenesis, which is of great importance to the treatment of cancer.