Nutritional Control of Cancer Cell Function by Amino Acids

氨基酸对癌细胞功能的营养控制

• 批准号: 9753749
• 负责人: MICHAEL S. KILBERG
• 金额: $ 33.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753749
• 关键词: Amino Acids; Apoptosis; Autophagocytosis; Binding; Binding Proteins; CCAAT-Enhancer-Binding Proteins; Cancer Control; Cancer and Nutrition; Cancerous; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Chemicals; Cultured Cells; DNA Binding; Deletion Mutagenesis; Development; Diet; Dietary Proteins; Disease; ELK1 gene; ETS Family Protein; Elements; Enhancers; Essential Amino Acids; Exhibits; Exonuclease; Family; Genes; Genetic Enhancer Element; Genetic Transcription; Genomics; Glioblastoma; Goals; Growth; Health; HepG2; Hepatocyte; Histidine; Human; Knock-out; Knowledge; Link; Liver neoplasms; MAP Kinase Gene; MEKs; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Modeling; Mus; Neonatal; Nude Mice; Nutrient; Nutritional; Operative Surgical Procedures; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Proliferating; Protein/Amino Acids Nutrition; Proteins; RNA, Transfer, Amino Acid-Specific; Ras/Raf; Recovery; Regulation; Research; Response Elements; Signal Pathway; Signal Transduction; Site; Testing; Tissues; Transfer RNA; Translations; Work; activating transcription factor; arm; c-myc Genes; cancer cell; elk-1 protein; experimental study; fetal; gene induction; genome-wide; innovation; jun Oncogene; knock-down; neoplastic cell; novel; public health relevance; response; sensor; small hairpin RNA; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor xenograft

 DESCRIPTION (provided by applicant): Protein or amino acid (AA) limitation activates an AA response (AAR) comprised of several partially characterized signaling pathways. The best studied of these involves AA sensing by GCN2 kinase and culminates in ATF4-dependent transcription via genomic C/EBP-ATF response element (CARE) enhancer sites that exhibit AAR element (AARE) function. Using HepG2 human hepatocellular carcinoma (HCC) and U87 human glioblastoma cells as models, our recent research indicates that there are GCN2/ATF4-independent pathways that exhibit little or no contribution in non-transformed cells. One of these pathways is mediated through the RAS/RAF/MEK/ERK arm of MAPK signaling and terminates with ELK1 transcription factor binding to ETS enhancer sequences not previously known to exhibit AARE function. We have discovered that the ERK pathway makes a significant contribution to the regulation of hundreds of AA-responsive genes in human HCC cells, but not in normal hepatocytes. These novel observations underscore the significant gaps in our knowledge about the impact of AA availability on basic cell functions. Our global hypothesis is that in some tumor cells the mammalian AAR extends beyond GCN2/ATF4 and that AA signaling via MAPK pathways is a significant component of the AAR, which permits tumor cells to proliferate despite AA limitation. The proposed experiments will test the following specific hypotheses in cultured cells and tumor-bearing mice. (Hypothesis I) An ERK pathway contributes to novel AA signaling independent of GCN2-ATF4. (Hypothesis II) The ERK AAR pathway includes transcription factors not previously known to be AA-responsive and terminates in novel genomic sequences that have functional AARE activity. (Hypothesis III) Induction of ERK-dependent signaling contributes to continued tumor growth despite AA limitation. The proposed studies are conceptually innovative for the following reasons. 1) The current dogma that the GCN2-ATF4 pathway induces most/all AA- responsive genes must be expanded to include an unknown AA sensor, MAPK signaling, and enhancer sequences previously unknown to have AARE activity. 2) AA-dependent transcription via ELK1 reveals an entirely new family of transcription factors, the ETS family, within the AAR. 3) The ERK-driven induction of genes, such as EGR1, FOS, JUN, and MYC, in AA-deprived tumor cells suggests a link between protein/AA nutrition and tumor proliferation.

 描述（由申请人提供）：蛋白质或氨基酸（AA）限制激活AA反应（AAR），该反应由几种部分表征的信号通路组成。其中最好的研究涉及GCN 2激酶的AA传感，并通过表现出AAR元件（AARE）功能的基因组C/EBP-ATF响应元件（CARE）增强子位点在ATF 4依赖性转录中达到高潮。以HepG 2人肝细胞癌（HCC）和U87人胶质母细胞瘤细胞为模型，我们最近的研究表明，在非转化细胞中存在GCN 2/ATF 4非依赖性通路，其贡献很小或没有贡献。这些途径之一是通过MAPK信号传导的RAS/RAF/MEK/ERK臂介导的，并以ELK 1转录因子与ETS增强子序列结合而终止，这些增强子序列先前不知道表现出AARE功能。我们已经发现ERK通路对人HCC细胞中数百个AA应答基因的调节做出了重要贡献，但在正常肝细胞中没有。这些新的观察结果强调了我们对AA可用性对基本细胞功能影响的知识存在重大差距。我们的总体假设是，在一些肿瘤细胞中，哺乳动物AAR延伸到GCN 2/ATF 4之外，并且通过MAPK途径的AA信号传导是AAR的重要组成部分，其允许肿瘤细胞增殖，尽管AA限制。拟议的实验将在培养的细胞和荷瘤小鼠中测试以下具体假设。（假设I）ERK途径有助于不依赖于GCN 2-ATF 4的新型AA信号传导。（假设II）ERK AAR途径包括先前不知道是AA-响应性的转录因子，并终止于具有功能性AARE活性的新基因组序列。（假设III）ERK依赖性信号传导的诱导有助于持续的肿瘤生长，尽管AA限制。拟议的研究在概念上具有创新性，原因如下。1)GCN 2-ATF 4途径诱导大多数/所有AA应答基因的当前教条必须扩展到包括未知的AA传感器、MAPK信号传导和先前未知的具有AARE活性的增强子序列。2)通过ELK 1的AA依赖性转录揭示了AAR内的一个全新的转录因子家族，ETS家族。3)ERK驱动的基因诱导，如EGR 1，FOS，JUN和MYC，在AA-剥夺肿瘤细胞表明蛋白质/AA营养和肿瘤增殖之间的联系。

项目成果

Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells.

• DOI: 10.1016/j.bbagrm.2018.01.002
• 发表时间: 2018-03
• 期刊: Biochimica et biophysica acta. Gene regulatory mechanisms
• 作者: Hayner JN;Shan J;Kilberg MS
• 通讯作者: Kilberg MS

Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells.

• DOI: 10.1016/j.tem.2017.07.003
• 发表时间: 2017-11
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Wortel IMN;van der Meer LT;Kilberg MS;van Leeuwen FN
• 通讯作者: van Leeuwen FN

Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.

• DOI: 10.3390/cancers12113267
• 发表时间: 2020-11-05
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Chiu M;Toscani D;Marchica V;Taurino G;Costa F;Bianchi MG;Andreoli R;Franceschi V;Storti P;Burroughs-Garcia J;Eufemiese RA;Dalla Palma B;Campanini N;Martella E;Mancini C;Shan J;Kilberg MS;D'Amico G;Dander E;Agnelli L;Pruneri G;Donofrio G;Bussolati O;Giuliani N
• 通讯作者: Giuliani N

Induction of early growth response gene 1 (EGR1) by endoplasmic reticulum stress is mediated by the extracellular regulated kinase (ERK) arm of the MAPK pathways.

内质网应激对早期生长反应基因 1 (EGR1) 的诱导是由 MAPK 通路的细胞外调节激酶 (ERK) 臂介导的。

• DOI: 10.1016/j.bbamcr.2018.09.009
• 发表时间: 2019
• 期刊: Biochimica et biophysica acta. Molecular cell research
• 作者: Shan,Jixiu;Dudenhausen,Elizabeth;Kilberg,MichaelS
• 通讯作者: Kilberg,MichaelS