ROLE OF CYTOPLASMIC P27KIP1 IN CELL MOTILITY AND METASTASIS

细胞质 P27KIP1 在细胞运动和转移中的作用

• 批准号: 7420770
• 负责人: STEVEN F DOWDY
• 金额: $ 0.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420770
• 关键词: actins; cell cycle proteins; cell motility; cytoplasm; enzyme inhibitors; metastasis; neoplasm /cancer; protein kinase; role

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Metastasic tumor growth is the principal event leading to death in patients with cancer, however, its molecular basis is presently poorly understood. Metastasic tumor cells generally migrate at a faster rate than normal cells or non-metastasic tumor cells. This observation leads to the hypothesis that increased cell motility (migration) is necessary for cells to become metastasic. Recently, a novel cytosolic-dependent role for the cyclin:CDK inhibitor p27KIP1 in cell motility was identified. It was shown that HGF signaling via the Met receptor resulted in the nuclear export of p27 KIP1 into the cytoplasm. This cytosolic localization was required for p27 KIP1 to induce cell motility and resulted in actin cytoskeletal rearrangements. These results suggest that deregulated signaling in tumor cells induce cytoplasmic import of p27. Our central hypothesis is that in the cytoplasm, p27 assembles into a complex involved in cytoskeletal remodeling and cell migration resulting in increased metastasis. The cytoplasmic relocalization and involvement of p27 in actin cytoskeletal rearrangement are evolutionarily reminiscent of alpha factor pheromone signaling in yeast. Far1p, the yeast cyclin:cdk inhibitor, mediates both a G1 cell cycle arrest in the nucleus and induction of shmoo formation in the cytoplasm that orients the actin cytoskeleton toward the opposite mating partner . In response to alpha factor, Far1p translocates from the nucleus to the cytoplasm and interacts with Cdc24p, a guanine nucleotide exchange factor for Cdc42p. Consistent with this functional analogy, mutation of a Far1p-like sequence motif present in the p27 scatter domain inactivates both cell migration and actin rearrangement, but preserves the cell cycle arrest functions of p27. Our objective is to identify the proteins complexes binding to p27 in the cytoplasm by TAP-tag purification and mass spectrometry analysis.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。转移性肿瘤生长是导致癌症患者死亡的主要事件，然而，其分子基础目前知之甚少。转移性肿瘤细胞通常比正常细胞或非转移性肿瘤细胞迁移速度更快。这一观察结果导致了这样的假设，即增加的细胞运动性（迁移）是细胞转移所必需的。最近，一种新的细胞周期蛋白：CDK抑制剂p27 KIP 1在细胞运动的cytosolic依赖的作用被确定。结果表明，通过Met受体的HGF信号传导导致p27 KIP 1的核输出到细胞质中。p27 KIP 1需要这种胞质定位来诱导细胞运动，并导致肌动蛋白细胞骨架重排。这些结果表明，在肿瘤细胞中的信号失调诱导p27的胞质输入。我们的中心假设是，在细胞质中，p27组装成一个复杂的参与细胞骨架重塑和细胞迁移，导致增加转移。肌动蛋白细胞骨架重排的细胞质重新定位和参与p27在进化上让人联想到α因子信息素信号在酵母中。Far 1 p，酵母细胞周期蛋白：cdk抑制剂，介导细胞核中的G1细胞周期停滞和细胞质中shmoo形成的诱导，其将肌动蛋白细胞骨架定向到相反的交配伴侣。响应α因子，Far 1 p从细胞核易位到细胞质，并与Cdc 24 p相互作用，Cdc 42 p的鸟嘌呤核苷酸交换因子。与这种功能类似，突变的Far 1 p样序列基序存在于p27散射域失活细胞迁移和肌动蛋白重排，但保留了细胞周期阻滞功能的p27。我们的目标是通过TAP标签纯化和质谱分析来鉴定细胞质中与p27结合的蛋白质复合物。