Regulation of LKB1 and AMPK Signaling by BRAF in Melanoma

描述（由申请方提供）：在约70%的人黑色素瘤中发现了蛋白激酶BRAF突变。在初步研究中，我发现致癌BRAF V600 E通过间接磷酸化LKB 1抑制肿瘤抑制因子LKB 1及其下游激酶AMPK的活性。此外，这种抑制对于具有BRAF V600 E突变的黑素瘤细胞的增殖是关键的。本研究的目的是充分了解BRAF信号对LKB 1和AMPK的调控，研究其在黑色素瘤发病机制中的相关性，并探讨其治疗意义。该提案将定义BRAF V600 E信号传导抑制LKB 1-AMPK活性的分子机制，将研究这种抑制性信号传导机制是否对小鼠异种移植模型中的黑素瘤细胞增殖和肿瘤生长至关重要，将研究人类黑素瘤中AMPK和ERK的活性状态之间的潜在相关性，将评估AMPK激活剂和MEK抑制剂联合治疗对黑色素瘤细胞增殖和异种移植肿瘤生长的影响，并最终将表征黑色素瘤中AMPK的关键下游信号蛋白。候选人：郑斌获得博士学位。2002年的分子病理学。他的职业目标是成为一名独立的科学家，在一个学术机构研究黑色素瘤发病机制的信号通路，重点是代谢信号及其翻译治疗意义。他将接受癌症生物学的高级培训，重点是黑色素瘤。他的赞助人刘易斯坎特利是脂质和蛋白激酶信号传导及其与癌症和代谢疾病相关性的专家。他的科学顾问委员会包括罗纳德德平霍，大卫费舍尔，琳达陈，斯科特格兰特和约翰阿萨拉，谁是癌症生物学，黑色素细胞和黑色素瘤生物学，黑色素瘤病理学和/或质谱专家。赞助商、咨询委员会和哈佛朗伍德医学区充满活力的科学环境将有助于郑博士实现他的科学和职业目标。摘要：黑色素瘤是最常见和最具侵袭性的癌症之一，2007年美国有约60，000例新发病例。本研究的目的是了解BRAF对代谢传感LKB 1-AMPK通路的调节，BRAF是黑色素瘤中最常见的突变基因之一。这项研究将为未来的黑色素瘤靶向治疗提供分子基础。

DESCRIPTION (provided by applicant): 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 of the tumor suppressor LKB1 and its downstream kinase AMPK through indirect phosphorylation on LKB1. Moreover, this inhibition is critical for the proliferation of melanoma cells with BRAF V600E mutation. The goal of this proposal is to fully understand the regulation of LKB1 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 LKB1-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. His career goal is to become an independent scientist at an academic institution studying the signaling circuitry underlying melanoma pathogenesis, with an emphasis on the metabolic signaling and its translational therapeutic implications. He will receive advanced training in cancer biology with a focus on melanoma. Lewis Cantley, his sponsor, is an expert in lipid and protein kinase signaling, and its relevance in cancer and metabolic diseases. His scientific advisory committee includes Ronald DePinho, David Fisher, Lynda Chin, Scott Granter and John Asara, who are experts in cancer biology, melanocyte and melanoma biology, melanoma pathology and/or MassSpec. The sponsor, the advisory committee and the vibrant scientific environment in the Harvard Longwood Medical Area will facilitate Dr. Zheng in achieving his scientific and career goals. LAY SUMMARY: Melanoma is one of the most common and aggressive cancers, with ~60,000 new cases in the US in 2007. The goal of this research is to understand the regulation of the metabolic sensing LKB1-AMPK pathway by BRAF, one of the most frequently mutated genes in melanoma. This research will provide the molecular basis for future targeted therapies for melanoma.