LKB1/AMPK signaling and Peutz-Jeghers syndrome

编码Ser/Thr蛋白激酶LKB 1的STK 11中的功能缺失突变负责 家族性错构瘤综合征，Peutz Jeghers综合征（PJS）。重要的是，最近的研究表明， STK 11在包括肺腺癌在内的多种人类癌症中的偶发突变。LKB1 磷酸化和激活AMP依赖性蛋白激酶，从而对能量应激起反应， 能量平衡的关键角色指导这一提议的假设是LKB 1-AMPK信号传导轴 进化到限制细胞生长的条件下，能源压力和遗传或表观遗传畸变， 以及抑制LKBI功能的转录和转录后事件，使肿瘤细胞 在能量压力下，它会超越通常限制细胞生长的代谢控制机制。总目标 该建议是阐明LKB，1-AMPK控制的信号传导和代谢网络，并使用此 信息，以确定缺乏LKB 1的肿瘤的治疗干预的目标。具体目标是：1） 利用上一个资助期开发的技术， LKB 1/AMPK信号网络中的靶点; 2）利用质谱代谢组学来鉴定代谢 在癌症中由于LKB 1的缺失而改变的途径，以及，3）使用基因工程小鼠 由于LKBI的缺失而发生癌症，在人类肺中观察到的其他遗传异常的背景下， 癌症，以评估基于目标1和2中的体外研究预测的药物或药物组合。

Loss of function mutations in STK11, encoding the Ser/Thr protein kinase, LKB1 are responsible for the familial hamartoma syndrome, Peutz Jeghers Syndrome (PJS). Importantly, recent studies have revealed sporatic mutations in STK11 in a variety of human cancers, including lung adenocarcinomas. LKB1 phosphorylates and activates AMP dependent protein kinase in response to energy stress and thus plays a key role in energy homeostasis. The hypothesis guiding this proposal is that the LKB1-AMPK signaling axis evolved to limit cell growth under conditions of energy stress and that genetic or epigenetic aberrations, as well as transcriptional and post-transcriptional events that suppress LKBI function, allow tumor cells to override metabolic control mechanisms that normally limit cell growth under energy stress. The overall goal ofthe proposal is to elucidate the signaling and metabolic network controlled by LKB,1-AMPK and use this information to identify targets for therapeutic intervention in tumors that lack LKB1. The specific aims are: 1) to utilize technologies developed during the previous granting period to identify druggable downstream targets in the LKB1/AMPK signaling network; 2) to utilize mass spec metabolomics to identify metabolic pathways that are altered in cancers that result from loss of LKB1 and, 3) to use genetically engineered mice that develop cancers due to loss of LKBI, in the context of other genetic aberrationslobserved in human lung cancers, to evaluate drugs or drug combinations, predicted on the basis of in vitro studies in Aims 1 and 2.