Regulation of LKB1 and AMPK Signaling by BRAF in Melanoma

在约70%的人类黑色素瘤中发现了蛋白激酶BRAF的突变。在初步研究中，我 已经发现致癌BRAF V600 E抑制肿瘤抑制因子LKB1及其受体的活性。 下游激酶AMPK通过对LKB1的间接磷酸化。此外，这种抑制对于 具有BRAF V600E突变的黑素瘤细胞的增殖。本提案的目标是充分了解 通过BRAF信号传导调节LKB1和AMPK，检查其在黑色素瘤发病机制中的相关性，并探索 其治疗意义。该提议将定义LKB1抑制的分子机制。 AMPK活性通过BRAF V600 E信号传导，将研究这种抑制性信号传导机制是否是关键的 黑色素瘤细胞增殖和小鼠异种移植模型中的肿瘤生长， 人类黑色素瘤中AMPK和ERK活性状态之间的相关性，将评估 AMPK激活剂和MEK抑制剂对黑色素瘤细胞增殖和异种移植的联合治疗 肿瘤生长，并最终将表征关键下游信号蛋白的AMPK在黑色素瘤。 候选人：郑斌获得博士学位。2002年在加州大学圣地亚哥分校的分子病理学和博士后 在哈佛医学院的刘易斯坎特利实验室接受培训。他的科学顾问委员会包括 Cory Abate-Shen，Richard Baer，Meenhard Herlyn和Ramon Parsons是癌症生物学专家， 信号传导和黑色素瘤。咨询委员会和哥伦比亚充满活力的科学环境 大学医学中心将协助郑博士实现他的科学和职业目标。

Mutations in the protein kinase BRAF have been found in ~70% of human melanoma. In preliminary studies, I have found that oncogenic BRAF V600E suppresses the activities ofthe tumor suppressor LKBl and its downstream kinase AMPK through indirect phosphorylation on LKBl. Moreover, this inhibition is critical for the proliferation of melanoma cells with BRAF V600E mutation. The goal of this proposal is to fiilly understand the regulation of LKBl and AMPK by BRAF signaling, examine its relevance in melanoma pathogenesis and explore its therapeutic implication. This proposal will define the molecular mechanism underlying the inhibition of LKBl- AMPK activity by BRAF V600E signaling, will investigate whether this inhibitory signaling mechanism is critical for melanoma cell proliferation, and tumor growth in mouse xenograft models, will examine the potential correlation between the active state of AMPK and ERK in human melanoma, will evaluate the effects of combined treatment of AMPK activators and MEK inhibitors on melanoma cell proliferation and xenograft tumor growth, and finally will characterize critical downstream signaling proteins of AMPK in melanoma. CANDIDATE: Bin Zheng received his Ph.D. in molecular pathology in 2002 from UC San Diego and postdoctoral trainings in the laboratory of Lewis Cantley at Harvard Medical School. His scientific advisory committee includes Cory Abate-Shen, Richard Baer, Meenhard Herlyn and Ramon Parsons, who are experts in cancer biology, cancer signaling and melanoma. The advisory committee and the vibrant scientific environment at the Columbia University Medical Center will facilitate Dr. Zheng in achieving his scientific and career goals.