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P53 and cell cycle checkpoint by p38 MAP kinase

p53 和 p38 MAP 激酶的细胞周期检查点

基本信息

批准号：
7161477
负责人：
Mercedes Rincon
金额：
$ 35.91万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-15 至 2008-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7161477
关键词：
76-kDa SH2 domain-containing leukocyte protein Address CD3 Antigens CD44 gene Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell Differentiation process Cells Complex DNA Damage DNA Repair DNA damage checkpoint Defect Dominant-Negative Mutation Fetal Thymic Organ Culture Figs - dietary Gene Targeting Generations Genes Growth Homeostasis Human IL2RA gene Immunologic Deficiency Syndromes In Vitro Interleukin-7 LCP2 gene Ligation MAP Kinase Signaling Pathways MAP2K6 gene MAPK14 gene Maps Mediating Modeling Mus Mutation Pathway interactions Phosphorylation Phosphotransferases Play Pre-Thymocyte Process Proto-Oncogenes Receptor Signaling Role Signal Transduction Staging Surface T Cell Receptor Signaling Pathway T-Cell Receptor T-Lymphocyte TP53 gene Testing Thymocyte Development Time Transgenic Mice Transgenic Organisms Up-Regulation V(D)J Recombination c-myc Genes cell type fetal human MAPK14 protein in vivo mitogen-activated protein kinase p38 prevent receptor expression repaired response thymocyte ultraviolet irradiation

项目摘要

Early thymocyte development (prior to the CD4+CD8 + stage) is critical for the generation of T cells. Genetic alterations that cause several human immunodeficiencies have been mapped in genes that play a key role in these early stages of thymocyte development. Several important processes occur during the differentiation of immature CD25¿CD44 - thymocytes into CD25-CD44- thymocytes, such as V(D)J recombination, expression of the T cell receptor (TcR)_ and expression of the pre-TcR complex. In addition to pre-TcR-mediated signals, inactivation of p53 appears to be required for differentiation of CD25+CD44 thymocytes. We have demonstrated that activation of p38 MAP kinase arrests cell cycle progression and differentiation of CD25¿CD44 - thymocytes. Moreover, we have also shown that p38 MAP kinase induces an accumulation of p53 in these thymocytes. It has been shown that p38 MAP kinase activates p53 in reponse to DNA damage to induce a cell cyle checkpoint for repair of mutations. We propose that the activation of p38 MAP kinase by IL-7 in CD25+CD44 - thymocytes phosphorylates and activates p53 to promote a G2/M checkpoint, a/lowing the repair of deleterious mutations that could be caused by V(D)J rearrangemetzt. Later, the expression of pre-TcR on CD25+CD44 - thymocytes triggers signals that inactivate p38 MAP kinase alld, thereby, p53 to allow cell cycle progression and further differentiation. To test this hypothesis we propose to demonstrate that: - p38 MAP kinase activates p53 at the CD25 +CD44- stage to induce a cell cycle chekpoint. We will examine: a) p53 phosphorylation and expression of 14-3-3(7 (a p53 target at the G2/M checkpoint) in thymocytes arrested at the CD25+CD44 - stage by activation of p38 MP kinase in vivo, and b) the effect of p53 inactivation in cell cycle progression and differentiation of these cells. - pre-TcR signals inactivate p38 MAP kinase and p53 to end the cell cycle checkpoint and allow differentiation of CD25+CD44 - thymocytes. We will examine p38 MAP kinase and p53 activity in CD25+CD44 - thymocytes in the presence or absence of pre-TcR or pre-TcR-signals. - IL-7 activates p38 MAP kinase and, thereby, p53 in CD25+CD44 thymocytes to induce a cell cycle checkpoint. - pre-TcR provides survival signals during the cell cycle checkpoint of CD25+CD44 - thymocytes to prevent death of these cells while DNA repairs takes place.

早期胸腺细胞发育（在CD 4 + CD 8+阶段之前）对于T细胞的产生至关重要。遗传导致几种人类免疫缺陷的改变已经定位在这些早期免疫缺陷中起关键作用的基因中。胸腺细胞发育的各个阶段。几个重要的过程发生在未成熟的分化 CD 25 <$CD44-胸腺细胞转化为CD 25-CD 44-胸腺细胞，如V（D）J重组，表达T细胞受体 (TcR)_和前TcR复合物的表达。除了前TcR介导的信号，p53的失活似乎是分化CD 25 + CD 44胸腺细胞所必需的。我们已经证明，p38 MAP激酶的激活可以阻止细胞周期的进展和分化。 CD 25 ~ CD 44-胸腺细胞。此外，我们还发现，p38 MAP激酶诱导p53的积累，这些胸腺细胞研究表明，p38 MAP激酶激活p53应答DNA损伤，诱导细胞凋亡。用于修复突变的周期检查点。我们认为IL-7对CD 25 + CD 44-T细胞中p38 MAP激酶的激活作用可能与IL-7对CD 25 + CD 44-T细胞中p38 MAP激酶的激活作用有关。胸腺细胞磷酸化并激活p53以促进G2/M检查点，降低有害细胞的修复。可能由V（D）J resistemetzt引起的突变。随后，CD 25 + CD 44-胸腺细胞上的pre-TcR表达触发信号，使p38 MAP激酶激活，从而使p53允许细胞周期进展，并进一步分化为了检验这一假设，我们建议证明： - p38 MAP激酶在CD 25 + CD 44-阶段激活p53以诱导细胞周期检查点。我们将研究：a） p53磷酸化和14-3-3（7）（p53在G2/M检查点的靶点）在胸腺细胞中的表达，通过在体内激活p38 MP激酶来诱导CD 25 + CD 44-期，和B）p53失活在细胞周期中的作用这些细胞的生长和分化。 - 前TcR信号转导p38 MAP激酶和p53以结束细胞周期检查点并允许分化 CD 25 + CD 44-胸腺细胞。我们将检测p38 MAP激酶和p53在CD 25 + CD 44-胸腺细胞中的活性。存在或不存在前TcR或前TcR信号。 - IL-7激活p38 MAP激酶，从而激活CD 25 + CD 44胸腺细胞中的p53，以诱导细胞周期检查点。 - 前TcR在CD 25 + CD 44-胸腺细胞的细胞周期检查点期间提供存活信号以防止死亡在DNA修复过程中，