Hsu Ya-Chieh, Chern Joshua J, Cai Yi, Liu Mingyao, Choi Kwang-Wook
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature. 2007 Feb 15;445(7129):785-8. doi: 10.1038/nature05528.
Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease.
在器官发生过程中，细胞生长和增殖是相互协调的。这些过程的失调会导致诸如癌症等病理状况。结节性硬化症（TSC）是一种由TSC1或TSC2肿瘤抑制基因突变引起的良性肿瘤综合征。对果蝇和其他生物体的研究已将TSC信号识别为一种保守的生长控制途径。TSC途径的激活由Rheb（脑中富集的Ras同源物）介导，Rheb是一种Ras超家族GTP酶。Rheb是TSC2的直接靶点，并受其GTP酶激活蛋白活性的负调控。然而，尚未鉴定出对Rheb进行正向调控所需的分子。在此我们表明，一种保守蛋白，即翻译控制肿瘤蛋白（TCTP），是TSC-Rheb途径的一个重要新组分。降低果蝇TCTP（dTCTP）水平会减小细胞大小、细胞数量和器官大小，这与果蝇Rheb（dRheb）突变体表型相似。dTCTP在遗传上对Tsc1和dRheb呈上位性，但作用于dRheb的下游靶点dS6k的上游。dTCTP直接与dRheb结合，并在体内和体外与其表现出鸟嘌呤核苷酸交换活性。与dTCTP相比，人TCTP（hTCTP）表现出相似的生化特性，并且可以挽救dTCTP突变体表型，这表明TCTP在TSC途径中的功能在进化上是保守的。我们的研究将TCTP鉴定为Rheb的直接调节因子以及TSC疾病的一个潜在治疗靶点。
