ATF4 is Downstream Effector of Bone Anabolic Growth Factors

ATF4 是骨合成代谢生长因子的下游效应器

• 批准号: 7172644
• 负责人: XIANGLI YANG
• 金额: $ 7.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172644
• 关键词: Accounting; Address; Affect; American; Binding; Biology; Bone Matrix; Bone Resorption; Bone Tissue; Bone remodeling; Cells; Coffin-Lowry syndrome; Collagen Type I; Condition; Cyclic AMP-Dependent Protein Kinases; Data; Degradation Pathway; Deterioration; Failure; Fracture; Future; Gene Silencing; Genes; Genetic; Genetic Transcription; Goals; Growth Factor; Health Sciences; Hip Fractures; Hormones; Innate Bone Remodeling; Insulin-Like Growth Factor I; Knowledge; Laboratories; Leucine Zippers; Life; Medicine; Mental Retardation; Modification; Mus; Mutate; Nuclear Protein; Nuclear Proteins; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid Hormones; Pathway interactions; Patients; Perinatal; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphorylation; Phosphotransferases; Predisposition; Protein Kinase; Protein Overexpression; Public Health; Research; Series; Serine; Signal Pathway; Signal Transduction; Skeletal Development; Skeletal system; Skeleton; Specificity; Staging; Testing; Texas; Therapeutic; Transactivation; Transgenic Mice; Universities; Vertebral column; Wrist; base; bone; college; cytokine; drug discovery; human PTH protein; improved; in vivo; mutant; novel; response; structural biology; transcription factor

DESCRIPTION (provided by applicant): The differentiation and function of osteoblasts are controlled by a series of incompletely defined growth factors, cytokines, hormones, and ultimately transcription factors that act in sequence. We have recently identified that ATF4 and its upstream regulator, RSK2, a kinase that, when mutated, causes Coffin-Lowry syndrome (CLS), a mental retardation condition associated with skeletal manifestations. Inactivation of Atf4 in mice causes severe osteoporosis. Mice lacking Rsk2 have similar skeletal abnormalities to that of CLS patients. In order to search for upstream regulators of ATF4 and RSK2, we tested IGF1, an important bone anabolic growth factor, and found that IGF1 induced the phosphorylation of RSK2 and ATF4. We have also observed that PKA, a downstream protein kinase of PTH, is also able to phosphorylate ATF4 and increase its transactivation ability. These data suggest that IGF1 and PTH use ATF4 as their transcription factor via the action of RSK2 or PKA to execute the anabolic function on osteoblasts. To test this hypothesis, we propose in this application with the following Specific Aims: 1. To analyze whether IGF1 and PTH activate RSK2 or PKA, which then phosphorylate ATF4 at serines 251 and 254, respectively, to enhance its transcription activity in osteoblasts. 2. To test whether phosphorylations of ATF4 accounts for its cell-specificity by increasing ATF4's stability in osteoblasts. 3. To establish transgenic mice overexpressing ATF4-S251A and ATF4-S254A, two mutant forms of ATF4 that are no longer phosphorylated by RSK2 and PKA, to study the functional relevance of RSK2- and PKA-phosphorylation in vivo. The knowledge gained from this study will improve our understanding of the mechanisms governing osteoblast differentiation, skeletal development and bone remodeling throughout life, as well as assist therapeutic drug discoveries in the future.

描述（由申请人提供）：成骨细胞的分化和功能是由一系列不完全确定的生长因子、细胞因子、激素以及最终顺序起作用的转录因子控制的。我们最近发现，ATF4及其上游调节因子RSK2是一种激酶，当发生突变时，会导致Coffin-Lowry综合征（CLS），这是一种与骨骼表现相关的智力迟钝状况。小鼠体内Atf4失活导致严重的骨质疏松症。缺乏Rsk2的小鼠与CLS患者具有相似的骨骼异常。为了寻找ATF4和RSK2的上游调控因子，我们检测了重要的骨合成代谢生长因子IGF1，发现IGF1诱导了RSK2和ATF4的磷酸化。我们还观察到PTH的下游蛋白激酶PKA也能磷酸化ATF4，提高ATF4的转激活能力。这些数据表明，IGF1和PTH通过RSK2或PKA的作用，以ATF4作为转录因子对成骨细胞执行合成代谢功能。为了验证这一假设，我们在本申请中提出以下具体目标：