Experimental pathologic study on the pathogenesis of cerebral lesions in tuberous sclerosis

硬化症（TSC）是由TSC 1或TSC 2基因突变引起的。TSC 2基因的蛋白质产物，块茎素，是胰岛素信号转导途径的负调节剂。tuberin的上游因子包括胰岛素、PI 3 K和Akt，tuberin的下游因子包括Rheb、mTOR、p70 S6 K和S6。先前的研究已经揭示，在人类TSC病变（肿瘤和错构瘤）中，块茎素的功能障碍导致mTOR通路的过度活化和S6的过度磷酸化。肿瘤的发生是根据两次打击假说。向上因子的活性，如PI 3 K和Akt，被假设为被反馈机制抑制。在大脑皮质的皮质结节样错构瘤中，没有第二次打击，并且已经指出了PI 3 K/Akt通路组成性激活的可能性。在本研究中，我们首先通过Eker大鼠的免疫组织化学研究来验证这些假设，Eker大鼠是一种由功能缺失突变引起的TSC动物模型， ...更多信息 Tsc 2基因的一部分。Eker大鼠大脑和肾脏的恶性肿瘤没有显示Akt的过度激活。在一小部分肿瘤细胞亚群中观察到mTOR和p70 S6 K的过度磷酸化。在大脑hamartia（皮质结节），有正常的Akt磷酸化，以及mTOR和p70 S6 K磷酸化的情况下，在反应性星形胶质细胞Akt和p70 S6 K的过度磷酸化。所有这些病变，无论是肿瘤还是错构瘤，都显示出明显的S6过度磷酸化。我们用Western印迹法检测了这些因子的磷酸化状态。肾脏（非癌组织）和大脑中Akt、tuberin、mTOR、p70 S6 K和S6的表达和磷酸化均正常。Eker大鼠肾癌组织中Akt低磷酸化，tuberin低表达，mTOR高表达，S6高磷酸化，而p70 S6 K无高磷酸化，提示该通路存在从下游到上游的负反馈机制，S6的激活是由p70 S6 K以外的其他因素引起的。少

Tuberous sclerosis complex (TSC) is caused by a mutation of either the TSC1 or TSC2 gene. The protein product of the TSC2 gene, tuberin, is a negative regulator of the insulin signal transduction pathway. Factors upstream of tuberin include insulin, PI3K and Akt, and those downstream of tuberin include Rheb, mTOR, p70S6K and S6. Previous studies have revealed that, in human TSC lesions (tumors and hamartias) dysfunction of tuberin causes hyper-activation of the mTOR pathway and over-phosphorylation of S6. Tumors occur according to the two-hit hypothesis. The activity of upward factors, such as PI3K and Akt, was hypothesized to be suppressed by a feedback mechanism. In hamartias like cortical tubers of the cerebral cortex, there is no second hit, and the possibility of constitutive activation of the PI3K/Akt pathway has been pointed out.In this study, we first examined these hypotheses by immunohistochemical studies of Eker rat, an animal model of TSC caused by a loss-of-function mutati … More on of the Tsc2 gene. Malignant tumors of the Eker rat cerebrum and kidneys showed no hyper-activation of Akt. The hyper-phosphorylation of mTOR and p70S6K was noted in a small subpopulation of tumor cells. In the cerebral hamartia (cortical tuber), there was normal Akt phosphorylation, as well as an absence of mTOR and p70S6K phosphorlation, in contrast to hyper-phosphorylation of Akt and p70S6K in reactive astrocytes. All these lesions, both tumors and hamartias, showed prominent hyper-phosphorylation of S6.We nest examined the phophorylation status of these factors by Western blotting. In the kidneys (non-cancerous tissues) and cerebrum, the expression and phosphorylation of Akt, tuberin, mTOR, p70S6K and S6 was normal. The renal cell cancer of Eker rats showed hypo-phosphorylation of Akt, low expression of tuberin, high expression of mTOR and hyper-phosphorylation of S6, but no hyper-phosphorylation of p70S6K.These results suggested a negative feedback mechanism from the downstream to the upstream of this pathway, and S6 activation by a factor other than p70S6K. Less