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LKB1/AMPK Signaling and Peutz-Jeghers Syndrome

LKB1/AMPK 信号转导和黑息综合征

基本信息

批准号：
7225433
负责人：
LEWIS C. CANTLEY
金额：
$ 46.37万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225433
关键词：
5&apos -AMP-activated protein kinase A Mouse AICA ribonucleotide AMP-activated protein kinase kinase Address Agonist Alanine Alleles Amino Acids Apoptosis Biochemical Biological Cancerous Cell Death Cell Line Cells Cholesterol Clinical Clinical Trials Collaborations Condition Cultured Cells Cyclic AMP-Dependent Protein Kinases DNA Damage Data Diabetes Mellitus Drosophila genus Elevation Embryo Ensure Environment Eukaryotic Cell Event Fatty Acids Fibroblasts Gene Mutation Generations Genes Genetic Genotype Glucose Glycogen Synthase Kinase 3 Goals Growth Growth Factor Growth Factor Receptors Hamartoma Human Immunohistochemistry Intervention Isotope Labeling Knock-in Mouse Laboratories Lead Lesion Malignant Neoplasms Mammalian Cell Mediating Metformin Mitogens Modality Modeling Modification Multiple Hamartoma Syndrome Mus Mutate Mutation Non-Insulin-Dependent Diabetes Mellitus Normal Cell Numbers Nutrient Oncogenes Organ Orthologous Gene Oxygen PTEN gene Pathway interactions Patients Peutz-Jeghers Syndrome Pharmacologic Substance Phenotype Phospho-Specific Antibodies Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Principal Investigator Protein Biosynthesis Protein Overexpression Protein-Serine-Threonine Kinases Proteins Proteome Proteomics Reagent Receptor Signaling Regulation Reporting Research Risk Role Route STK11 gene Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Site Specimen Stimulus Stress Syndrome System TP53 gene TSC1 gene TSC2 gene Techniques Testing Therapeutic Therapeutic Intervention Thinking Tissues Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Ursidae Family Work base cell growth cell type deprivation diabetic human FRAP1 protein in vivo lung Carcinoma mTOR Inhibitor mTOR inhibition mimetics mouse model mutant neoplastic cell novel novel strategies programs response role model rosiglitazone skills small hairpin RNA stoichiometry tumor tumor xenograft uncontrolled cell growth vector

项目摘要

Project 2: LKB1/AMPK signaling and Peutz-Jeahers syndrome. The focus of this project is to further elucidate the signal transduction pathways that inhibit hamartomas formation in humans, focusing on the recently discovered role of the LKB1 tumor suppressor in regulating mTOR signaling via the TSC proteins. The LKB1 tumor suppressor is a serine/threonine kinase which directly phosphorylates and activates the AMP-activated protein kinase (AMPK). Through its regulation of AMPK, LKB1 serves as an low energy checkpoint that controls the response of normal cells and tumor cells to conditions of low glucose and low oxygen. We previously showed this effect is due in part to AMPK induced activation of the TSC2 tumor suppressor and subsequent inhibition of mTOR signaling. We speculate that loss of this normal checkpoint on cell growth is not only critically disrupted in hamartomas, but also in a variety of sporadic tumors. Finally, we have found that cells lacking the LKB1/AMPK/TSC2 pathway are uniquely sensitized to apoptosis following energy deprivation. We anticipate that therapeutic interventions exploiting these findings will be of broad utility, given that agents which confer those effects are already in widespread clinical use as anti-diabetic modalities.

项目 2：LKB1/AMPK 信号传导和 Peutz-Jeahers 综合征。该项目的重点是进一步阐明抑制信号转导途径人类错构瘤的形成，重点关注最近发现的 LKB1 肿瘤的作用通过 TSC 蛋白调节 mTOR 信号传导的抑制剂。 LKB1 肿瘤抑制因子是丝氨酸/苏氨酸激酶直接磷酸化并激活 AMP 激活蛋白激酶（AMPK）。通过对 AMPK 的调节，LKB1 充当低能量检查点，控制正常细胞和肿瘤细胞对低葡萄糖和低氧条件的反应。我们之前表明这种效应部分是由于 AMPK 诱导 TSC2 肿瘤的激活 mTOR 信号传导的抑制剂和随后的抑制。我们推测失去这种正常的细胞生长的检查点不仅在错构瘤中受到严重破坏，而且在多种细胞生长中也受到严重破坏。散发性肿瘤。最后，我们发现缺乏LKB1/AMPK/TSC2通路的细胞对能量剥夺后的细胞凋亡特别敏感。我们预计治疗利用这些发现的干预措施将具有广泛的效用，因为赋予这些发现的因素其效果已作为抗糖尿病方式广泛应用于临床。