Mechanisms of PTEN-Long Function in Cancer

PTEN-长功能在癌症中的机制

基本信息

批准号：
8671717
负责人：
Ramon E Parsons
金额：
$ 35.07万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8671717
关键词：
3&apos Untranslated Regions Affect Amino Acids Animal Model Animals Binding Brain Neoplasms Cancer Biology Cancer Patient Cancer cell line Cell Cycle Arrest Cell Death Cell division Cell membrane Cell secretion Cell surface Cells Chimeric Proteins Chromosomes Cleaved cell Complementary DNA Data Development Drug or chemical Tissue Distribution Enzyme Inhibition Epigenetic Process Exons Gene Activation Germ-Line Mutation Half-Life Hamartoma Human Initiator Codon Laboratories Length Lipids Malignant Neoplasms Mammary Neoplasms Mediating Messenger RNA MicroRNAs Missense Mutation Modeling Mus Mutate Mutation Names Normal tissue morphology Oncogenes Open Reading Frames Output PTEN gene PTEN protein Penetration Peptide Signal Sequences Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Property Protein Isoforms Proteins Proto-Oncogene Proteins c-akt RNA Splicing Reading Frames Recombinants Resistance Second Messenger Systems Signal Transduction Somatic Mutation Tail Testing Therapeutic Tissues Transcript Translating Travel Tumor Cell Line Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Tumor-Associated Process Tumor-Derived Variant Vertebrates base cancer cell caspase-3 cell growth cell motility in vivo inositol 3-phosphate migration mutant neoplastic cell novel novel strategies polyarginine polypeptide promoter public health relevance red fluorescent protein restoration second messenger tool tumor tumor growth tumor xenograft uptake vector

项目摘要

DESCRIPTION (provided by applicant): Cancers develop as a result of inactivation of tumor suppressor genes and activation of oncogenes. PTEN is one of the most frequently inactivated tumor suppressor genes in human cancer. The PTEN gene is approximately 100,000 bp in size and is located on chromosome 10q23. PTEN mRNA is transcribed from a single promoter, spliced together from 9 exons, and varies from 2-6 kb in length based upon the length of its 3' untranslated region. The transcripts all contain a 403 amino acid open reading frame that encodes the PTEN protein, which is composed of a phosphatase, C2 and tail domains. The PTEN protein encodes a lipid phosphatase that removes the 3' phosphate from the inositol ring of phosphoinositol-3, 4, 5-trisphosphate (PIP3). PTEN can be inactivated in cancers by a variety of alterations that include missense mutation, homozygous deletion, transcript silencing, and enzyme inhibition. Recent examination of the 5' end of the PTEN transcript cDNA indicated the potential for a CTG initiation codon capable of translating a 576 amino acid open reading frame in the same reading frame as classical PTEN protein, such that it would contain an amino-terminal 173 amino acid alternatively translated domain followed by a phosphatase, C2 and tail domain. Comparison of different animal species indicated that the alternatively translated domain was highly conserved among vertebrates. Expression of the full length cDNA in cells led to the expression of 75 kDa and 56 kDa protein bands, which were dependent upon intact initiation codons for their respective expression. Examination of the 173 amino acid alternatively translated domain revealed that it had a secretion signal sequence and a cell penetration polyarginine sequence. The 75 kDa form of PTEN, which we have named PTEN-Long, could be secreted from cells and displayed cell penetrating activity. Once inside the cell, PTEN-Long was able to inhibit signaling to AKT and regress tumor growth. Moreover, a PTEN-Long Red Fluorescent Protein fusion protein was able to enter cells. Based upon these preliminary data, we propose to better understand how tumor mutations affect PTEN-Long secretion, cell binding, uptake and PIP3 signaling and examine its tumor suppressive and fused cargo delivery capacities.

描述（由申请人提供）：由于肿瘤抑制基因失活和致癌基因的激活而发展。 PTEN是人类癌症中最常见的肿瘤抑制基因之一。 PTEN基因的大小约为100,000 bp，位于10q23染色体上。 PTEN mRNA是从单个启动子转录的，从9个外显子剪接在一起，根据其3'未翻译区域的长度从2-6 kb的长度变化。这些转录物都包含一个编码PTEN蛋白的403个氨基酸开放式阅读框，该蛋白由磷酸酶，C2和尾巴结构域组成。 PTEN蛋白编码一种脂质磷酸酶，该脂质磷酸酶从磷酸辛醇3、4、5-三三磷酸磷酸盐的肌醇环中去除3'磷酸盐（PIP3）。 PTEN可以通过包括错义突变，纯合缺失，转录本沉默和酶抑制的各种改变在癌症中灭活。对PTEN转录cDNA的5端的最新检查表明，与经典的PTEN蛋白相同的阅读框架中的CTG启动密码子可以转换576个氨基酸开放式阅读框架，因此它将包含173氨基末端173氨基酸氨基酸替代翻译的结构域，然后是磷酸酶，C2和尾部域。对不同动物物种的比较表明，替代翻译的结构域在脊椎动物中是高度保守的。全长cDNA在细胞中的表达导致了75 kDa和56 kDa蛋白带的表达，这取决于其各自表达的完整起始密码子。对173个氨基酸的检查交换结构域，表明它具有分泌信号序列和细胞穿透多精氨酸序列。我们命名为PTEN-LONG的75 kDa形式可以从细胞中分泌并显示细胞穿透活性。一旦进入细胞，Pten-long能够抑制对AKT的信号传导并回归肿瘤的生长。此外，PTEN长的红色荧光蛋白融合蛋白能够进入细胞。基于这些初步数据，我们建议更好地了解肿瘤突变如何影响长时间的分泌，细胞结合，摄取和PIP3信号传导，并检查其肿瘤抑制和融合的货物递送能力。