Regulation of LKB1 and AMPK Signaling by BRAF in Melanoma

描述(由申请人提供)：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，我发现致癌的BRAF V600E通过间接磷酸化LKB1抑制肿瘤抑制基因LKB1及其下游的激酶AMPK的活性。此外，这种抑制对于携带BRAF V600E突变的黑色素瘤细胞的增殖至关重要。本研究的目的是全面了解BRAF信号对LKB1和AMPK的调控，研究其在黑色素瘤发病机制中的作用，并探讨其治疗意义。这项建议将确定BRAF V600E信号抑制LKB1-AMPK活性的分子机制，将研究这一抑制信号机制是否对黑色素瘤细胞增殖和肿瘤生长至关重要，将研究AMPK的激活状态与ERK在人黑色素瘤中的潜在相关性，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肿瘤生长的影响，最终将表征AMPK在黑色素瘤中的关键下游信号蛋白。候选人：郑斌，2002年获得分子病理学博士学位。他的职业目标是成为一家学术机构的独立科学家，研究黑色素瘤发病机制背后的信号电路，重点是代谢信号及其翻译治疗意义。他将接受癌症生物学方面的高级培训，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及其与癌症和代谢性疾病的相关性方面的专家。他的科学顾问委员会包括Ronald DePinho、David Fisher、Lynda Chin、Scott Granter和John Asara，他们是癌症生物学、黑素细胞和黑色素瘤生物学、黑色素瘤病理学和/或MassSpec方面的专家。赞助商、顾问委员会和哈佛大学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。报道摘要：黑色素瘤是最常见和最具侵袭性的癌症之一，2007年美国约有60,000例新病例。本研究的目的是了解在黑色素瘤中最常见的突变基因之一BRAF对代谢感应LKB1-AMPK通路的调节作用。这项研究将为未来黑色素瘤的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.