HIF-1

HIF-1

• 批准号: 7602894
• 负责人: ERICA A. GOLEMIS
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602894
• 关键词: Actins; Actomyosin; Adhesives; Affect; Apoptosis; Architecture; Biological Process; Cell Adhesion Process; Cell Cycle Progression; Cell Shape; Cell division; Cells; Centrosome; Cessation of life; Compatible; Computer Retrieval of Information on Scientific Projects Database; Cues; Cyclin B; Cytokinesis; Defect; Development; Excision; Failure; Family; Focal Adhesions; Funding; Goals; Grant; Growth; Institution; Integrins; Interphase; Length; Licensing; Localized; Mediator of activation protein; Mitosis; Mitotic; Mitotic spindle; Process; Proteins; Regulation; Reporting; Research; Research Personnel; Resources; Role; Shapes; Signal Transduction; Signaling Protein; Site; Source; System; United States National Institutes of Health; Work; base; cell motility; human BCAR1 protein; interest; migration; receptor; response; scaffold

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. The shape of a cell is determined primarily by its internal actin cytoskeletal architecture and influenced by focal adhesions, which constitute points of linkage between the extracellular matrix (ECM), the integrin receptor system and actin scaffolds. In response to external adhesive signals or internally generated cues, cells rearrange their actin cytoskeletal networks, thereby altering assembly of integrin-associated signal-transducing networks. Critical biological processes affected by the combined changes in cell shape and signal transduction include cell migration, proliferation, transformation and apoptosis, making the elucidation of the mechanisms involved of considerable interest. HEF1, and the related proteins p130Cas and Efs/Sin, define the Cas (Crk-associated substrate) family of focal adhesion-associated signaling proteins. Mechanistic studies of these proteins has defined their roles in the processes of cell adhesion and cell migration, and outlined a set of upstream inducers and downstream mediators of their function. However, our work has also demonstrated that HEF1 possesses additional unique activities relevant to apoptosis and cell division. These discrete activities derive from the function of processed forms of HEF1. A 28 kD carboxyterminal form induces cellular rounding and initiates p53-dependent death signaling under some growth circumstances, opposing a pro-survival activity of p130Cas. Intriguingly, a 55 kD aminoterminal HEF1 form arising in mitosis translocates to the mitotic spindle; and we have recently determined that altering the expression level and ratios between different forms of HEF1 so as to increase abundance of full length HEF1 versus the 55 kD form results in a failure of mitosis that involves development of multipolar spindles, failure of abscission at cytokinesis, and accumulation of cells at G1. This suite of defects is compatible with defects reported for proteins involved in functions at the centrosome, based on activities that include regulation of cyclin B stability, and licensing of abscission through centrosomal migration to the site of cytokinesis and delivery of proteins such as p160ROCK that control actomyosin ring contractile function. We have also determined that endogenous HEF1 localizes to the centrosome, and further shown that mis-expressed HEF1 affects cyclin B accumulation and activation of RhoA, a p160ROCK activator. Based on these and other results, we propose that HEF1 has a unique function as a regulator of cell cycle progression through mitosis and cytokinesis, and that this effect is separable from its roles in attachment-related survival signaling. Our goal is to determine whether HEF1 uses common or unique effectors for its functions in interphase versus mitotic cells.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 细胞的形状主要取决于其内部肌动蛋白细胞骨架结构，并受焦点粘连的影响，局灶性粘连构成细胞外基质（ECM），整联蛋白受体系统和肌动蛋白支架之间的联系点。 为了响应外部粘合信号或内部生成的提示，细胞重新排列其肌动蛋白细胞骨架网络，从而改变了整合素相关信号传递网络的组装。 受细胞形状和信号转导的综合变化影响的关键生物学过程包括细胞迁移，增殖，转化和凋亡，从而阐明了引起了相当有趣的机制。 HEF1，以及相关的蛋白质P130CA和EFS/SIN定义了粘着斑相关信号蛋白的CAS（与CRK相关的底物）家族。这些蛋白质的机械研究定义了它们在细胞粘附和细胞迁移过程中的作用，并概述了一组上游诱导剂和其功能下游介体。 但是，我们的工作还表明，HEF1具有与细胞凋亡和细胞分裂有关的其他独特活动。 这些离散活动来自HEF1的处理形式的功能。 28 kd的羧基末端形式诱导细胞圆形，并在某些生长环境下启动p53依赖性死亡信号传导，反对P130CAS的亲寿命活性。有趣的是，有丝分裂引起的55 kD aminoterminal HEF1形式转移到有丝分裂的纺锤体上。并且我们最近确定，改变了不同形式的HEF1之间的表达水平和比率，以增加HEF1的丰度与55 kD形式相比，导致有丝分裂失败，涉及多极纺锤体的发展，细胞因子在细胞因子上的脱落失败以及G1处的细胞积累。 这套缺陷套件与报道的中心体功能蛋白报道的缺陷是基于调节细胞周期蛋白B稳定性的活性，以及​​通过中心体迁移到细胞因子位点的脱发和蛋白质递送（例如P160ROCK）控制Actomyosin actomyososososososososososososososososososososososososososososososososososososososososososososososososososososososososs contransive蛋白质的许可。 我们还确定内源性HEF1定位于中心体，并进一步表明，误表达的HEF1会影响细胞周期蛋白B的积累和RhoA的激活，RhoA是P160ROCK激活剂。 基于这些和其他结果，我们建议HEF1通过有丝分裂和细胞因子具有独特的功能作为细胞周期进展的调节剂，并且这种效应与其在依恋相关的生存信号中的作用可分开。 我们的目标是确定HEF1是否使用常见或独特的效应子来实现相间和有丝分裂细胞的功能。