Regulation of LKB1 and AMPK Signaling by BRAF in Melanoma

在大约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 发现致癌基因BRAF V600E抑制肿瘤抑制基因LKB1及其活性 通过间接磷酸化LKB1下游的AMPK。此外，这种抑制对于 BRAF V600E突变对黑色素瘤细胞增殖的影响这项建议的目标是充分理解 BRAF信号对LKB1和AMPK的调控，探讨其在黑色素瘤发病机制中的作用 它的治疗意义。这一提议将确定抑制LKB1-的分子机制。 AMPK活性的BRAF V600E信号，将调查这一抑制信号机制是否关键 对于黑色素瘤细胞的增殖，以及肿瘤在小鼠异种移植模型中的生长，将会检验其潜力 AMPK活性状态与ERK在人黑色素瘤中的相关性，将评估 AMPK激活剂和MEK抑制剂联合应用对黑色素瘤细胞增殖和移植瘤的影响 肿瘤生长，最后将表征黑色素瘤中AMPK的关键下游信号蛋白。 候选人：郑斌2002年在加州大学圣地亚哥分校获得分子病理学博士学位，博士后 在哈佛医学院刘易斯·坎特利的实验室里进行的培训。他的科学顾问委员会包括 科里·阿巴特-申、理查德·贝尔、米哈德·赫林和雷蒙·帕森斯，他们是癌症生物学、癌症 信号和黑色素瘤。咨询委员会和哥伦比亚大学充满活力的科学环境 大学医学中心将帮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.