Control of Skeletal Growth by ATF-2

ATF-2 对骨骼生长的控制

• 批准号: 6777709
• 负责人: PHYLLIS A. LUVALLE
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777709
• 关键词: BCL2 gene /protein; apoptosis; biological signal transduction; bone development; cAMP response element binding protein; cell growth regulation; cell proliferation; chondrocytes; chondrodystrophy; fibroblast growth factor; flow cytometry; gel mobility shift assay; gene expression; genetic transcription; genetically modified animals; growth factor receptors; laboratory mouse; retinoblastoma protein

DESCRIPTION (provided by applicant): Control of growth plate chondrocyte progression is essential for proper bone and marrow formation. Disruptions in several genes such as those for the PTHrP receptor, FGFR3 receptor, TGF beta receptor type II, vitamin D receptor, and thyroid hormone receptor result in disorganization of the growth plate and abnormal endochondral ossification in mice. Multiple human genetic and acquired skeletal disorders result from the perturbation of the balance between chondrocyte proliferation and maturation in the growth plate, including chondrodysplasias, overgrowth diseases like Beckwith Wiedernann syndrome, osteochondromas and other cartilage neoplasms, and some forms of osteoarthritis. Activating transcription factor 2 (ATF-2) targets the cyclic AMP response element (CRE) in many different genes and results in the activation of gene transcription. A mutation in the ATF-2 gene in mice results in the absence fo ATF-2 in growth plate chondrocytes and defects in endochondral ossification resembling human hypochondroplasia, a dwarfism due to activating mutations in the FGFR3 receptor. ATF-2-deficient mice have a substantially reduced survival rate, and display a growth plate phenotype that encompasses reductions in both the proliferative and hypertrophic zones. The overall goal of this proposal is to define the roles of ATF-2 in control of chondrocyte proliferation and growth plate progression. The proposal is focused on eight gene targets of ATF-2: those for cyclin D1, cyclin A, c-Fos, c-Jun, the retinoblastoma protein (pRb), p107, p130,and Bcl-2. All but Bcl-2 are directly involved in cell cycle progression, and therefore are regulators of chondrocyte proliferation. Bcl-2 plays a role in the control of apoptosis, which occurs in the terminal chondrocytes of the hypertrophic zone in the growth plate. This proposal exploits the growth plates of ATF-2-deficient mice for molecular analyses of 1) the direct and indirect effects of ATF-2 on target genes; 2) the consequences of reductions in expression of the target genes in the absence of ATF-2; and 3) the definition of signaling pathways that result in normal I or abberant growth plate chondrocyte proliferation and progression.

描述（由申请人提供）：生长板软骨细胞进展的控制对于适当的骨和骨髓形成至关重要。一些基因的破坏，例如 PTHrP 受体、FGFR3 受体、II 型 TGF β 受体、维生素 D 受体和甲状腺激素受体的基因的破坏，会导致小鼠生长板的紊乱和软骨内骨化的异常。多种人类遗传性和后天性骨骼疾病是由于生长板中软骨细胞增殖和成熟之间的平衡扰乱造成的，包括软骨发育不良、过度生长疾病（如贝克威斯·韦德南综合征）、骨软骨瘤和其他软骨肿瘤，以及某些形式的骨关节炎。激活转录因子 2 (ATF-2) 以许多不同基因中的环 AMP 反应元件 (CRE) 为目标，导致基因转录激活。小鼠 ATF-2 基因突变导致生长板软骨细胞中 ATF-2 的缺失以及软骨内骨化缺陷，类似于人类软骨发育不全，这是一种由于激活 FGFR3 受体突变而导致的侏儒症。 ATF-2缺陷小鼠的存活率显着降低，并表现出生长板表型，包括增殖区和肥大区的减少。该提案的总体目标是确定 ATF-2 在控制软骨细胞增殖和生长板进展中的作用。该提案重点关注 ATF-2 的八个基因靶点：细胞周期蛋白 D1、细胞周期蛋白 A、c-Fos、c-Jun、视网膜母细胞瘤蛋白 (pRb)、p107、p130 和 Bcl-2。除 Bcl-2 外，所有其他蛋白都直接参与细胞周期进程，因此是软骨细胞增殖的调节因子。 Bcl-2在控制细胞凋亡中发挥作用，细胞凋亡发生在生长板肥大区的终末软骨细胞中。该提案利用 ATF-2 缺陷小鼠的生长板进行以下分子分析：1）ATF-2 对靶基因的直接和间接影响； 2) 在没有 ATF-2 的情况下靶基因表达减少的后果； 3) 导致正常 I 或异常生长板软骨细胞增殖和进展的信号通路的定义。